JP2013545786A - Azabenzimidazole as an antiviral agent for respiratory syncytial virus - Google Patents

Abstract

式Ｉを満たす化合物、またはそのプロドラッグ、Ｎ−オキシド、付加塩、第四級アミン、金属複合体もしくは立体化学的異性体形態物：これらの化合物を有効成分として含有する組成物、これらの化合物および組成物の製造方法。
【選択図】 なし[Chemical 1]

Compounds satisfying Formula I, or prodrugs, N-oxides, addition salts, quaternary amines, metal complexes or stereochemically isomeric forms: compositions containing these compounds as active ingredients, these compounds And a method for producing the composition.
[Selection figure] None

Description

  The present invention relates to azabenzimidazoles having antiviral activity, in particular, inhibitory activity against replication of respiratory syncytial virus (RSV). The present invention further relates to the preparation of these azabenzimidazoles, compositions comprising these compounds and these compounds for use in the treatment of respiratory syncytial virus infection.

  Human RSV or respiratory syncytial virus, along with bovine RSV, is a giant RNA virus belonging to the Pneumovirus subfamily of the Paramyxoviridae family. Human RSV is responsible for a spectrum of airway diseases in people of all ages worldwide. It is a major cause of lower respiratory tract disorders during neonatal and childhood. More than half of the newborns encounter RSV early in their lifetime and within their first two years. Infection in younger children can cause lung injury that persists for several years and can contribute to chronic lung disease (asthma with zyzey) in later life. Older children and adults often suffer from (malignant) common colds due to RSV infection. In old age, again, susceptibility has increased and RSV has been associated with many outbreaks of senile pneumonia resulting in significant death.

  Infection of viruses from certain subgroups does not protect against subsequent infection by RSV isolates from the same subgroup in the next winter. Thus, RSV reinfection is commonplace, although only two subtypes A and B are present.

  Today, only three drugs are approved for use against RSV infection. The first one is the nucleotide analog ribavirin, which provides aerosol therapy for severe RSV infection in hospitalized children. This aerosol route of administration, toxicity (risk of malformation heritability), cost and highly variable efficacy limit its use.

Two other drugs, Respigam (RespiGam® (RSV-IG)) and Synagis (Synagis® parivizumab), polyclonal and monoclonal antibody immunostimulants are intended for use in protective methods Has been. Both are very expensive and require parenteral administration. All other attempts to develop a safe and effective RSV vaccine have so far failed. Inactivated vaccines failed to protect against the disease, and in some cases, the disease was enhanced during subsequent infections. Live attenuated vaccines have been tried with limited success. Clearly, there is a need to provide an agent that is non-toxic and simple to administer that is effective against RSV replication. It would be particularly preferred to provide an agent for RSV replication that can be administered orally. Patent Document 1, whose title is “imidazopyridine and imidazopyrimidine antiviral agent”, is actually related to benzimidazole antiviral agent. The compounds in the literature are offered as having antiviral activity with EC ₅₀ values that range from as high as 0.001 μM to as high as 50 μM (which usually does not exhibit the desired biological activity). . Another document is US Pat. No. 6,057,056, which relates to active substituted 2-methylbenzimidazole RSV antiviral agents within the same scope. Another related background document for active compounds within the same scope is US Pat. The literature on the relationship between structure and activity is related to RSV inhibition of 5-substituted benzimidazole compounds.

It is desired to provide a new drug having antiviral activity. In particular, it would be desirable to provide new agents that have RSV replication inhibitory activity. In addition, compounds of the order of magnitude within the stronger range of the prior art (ie the bottom of the range up to 50 μM above), preferably at about the highest activity level, more preferably disclosed in the prior art document It would be desirable to modify the compound structure to make it possible to obtain antiviral biological activity, even of a stronger activity. Even more desirable is to find compounds with oral antiviral activity.

WO 01/95910 WO 03/053344 WO 02/26228

X. A. Wang et al, Bioorganic and Medicinal Chemistry Letters 17 (2007) 4592-4598

  In order to better handle one or more of the above desires, one aspect of the present invention is an antiviral azabenzimidazole compound of formula I, or a prodrug, N-oxide, addition salt, quaternary A secondary amine, metal complex or stereochemical isomer form is provided.

Wherein each X is independently C or N, and at least one X is N;
Each Y is independently C or N;
R ₁ is present when X is C, and R ₁ is H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, N (R ₅ ) ₂ , CO (R ₆ ), CH ₂ NH ₂ , CH ₂ OH, CN, C (═NOH) H ₂ , C (═NOCH ₃ ) NH ₂ , C (═NH) NH ₂ , CF ₃ , OCF ₃ and B (OH) ₂ ; selected from the group of B (O—C ₁ -C ₆ alkyl) ₂ ;
R ₁ is not present when X is N,
R ₂ is — (CR ₇ R ₈ ) _n —R ₉ ,
R ₃ is selected from the group consisting of H, C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₁₀ alkenyl, SO ₂ -R ₇ , CH ₂ CF ₃ , or contains an oxygen atom A 4-6 membered saturated ring;
R ₄ is present when Y is C and is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, CO (R ₇ ), COO (R ₇ ). Selected from the group consisting of CF ₃ and halogen;
R ₅ is selected from the group consisting of H, C ₁ -C ₆ alkyl, COOCH ₃ and CONHSO ₂ CH ₃ ;
R ₆ is OH, O (C ₁ -C ₆ alkyl), NH ₂ , NHSO ₂ N (C ₁ -C ₆ alkyl) ₂ , NHSO ₂ NHCH ₃ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ Selected from the group consisting of (C ₃ -C ₇ cycloalkyl) and N (C ₁ -C ₆ alkyl);
R ₇ and R ₈ are each independently selected from H, C ₁ -C ₁₀ alkyl and C ₃ -C ₇ cycloalkyl, or R ₇ and R _{8 taken} together are N, S, O Forming a 4- to 6-membered aliphatic ring optionally containing a heteroatom selected from:
R ₉ is H, R ₁₀ , C ₁ -C ₆ alkyl, OH, CN, F, CF ₂ H, CF ₃ , CONR ₇ R ₈ , COOR ₇ , CON (R ₇ ) SO ₂ R ₈ , CON (R _{7) SO 2 N (R 7} R 8), NR 7 R 8, NR 7 COOR 8, OCOR 7, O- _{benzyl, NR 7 SO 2 R 8,} SO 2 NR 7 R 8, SO 2 R 7, OCONR 7 R ₈ , OCONR ₇ R ₁₀ , N (R ₇ ) CON (R ₇ R ₈ ), N (R ₇ ) COOR ₁₀ ; containing phthalimide, 2-methyl-benzothiophene (1,1) dioxide, or oxygen atom Selected from the group consisting of 4-6 membered saturated rings;
n is an integer from 2 to 6;
R ₁₀ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridine or pyrazole, which are optionally selected from CF ₃ , CH ₃ , OCH ₃ , OCF ₃ or halogen. May be substituted with one or more substituents.

In some embodiments of the invention, R ₃ is H, C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₁₀ alkenyl, SO ₂ -R ₇ , or a 4-6 member containing oxygen Selected from the group consisting of saturated rings, and R ₉ is H, C ₁ -C ₆ alkyl, OH, CN, F, CF ₂ H, CF ₃ , COR ₇ R ₈ , COOR ₇ , CON (R ₇ ) SO _{2 R 8, CON (R 7} ) SO 2 N (R 7 R 8), NR 7 R 8, NR 7 COOR 8, OCOR 7, O- _{benzyl, NR 7 SO 2 R 8,} SO 2 R 7 R 8, Selected from the group consisting of SO ₂ R ₇ or a 4-6 membered saturated ring containing an oxygen atom;
n is an integer of 2-6.

  In another aspect, the present invention relates to said compound for use in the treatment of RSV infection in warm-blooded animals, preferably humans. In yet another aspect, the invention provides a method of treating viral RSV infection in a patient in need, comprising administering to the patient an effective amount of a compound as defined above. In yet another aspect, the invention resides in the use of the above compound for the manufacture of a medicament in the treatment of RSV infection.

  In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable adjuvant.

  In yet a further aspect above, the present invention provides a process for the preparation of a compound as defined above.

DETAILED DESCRIPTION OF THE INVENTION The molecules of formula I in derivatives from the prior art have an azabenzimidazole moiety substituted on one side (left side in the depicted formula). The present invention is based on the thoughtful recognition that, in a broad concept, these substituted azabenzimidazole compounds generally have interesting RSV inhibitory activity. In addition, these compounds are accessible to anti-RSV activity in the higher region of the range available in the literature (ie, lower terminal EC ₅₀ values). In particular, on the basis of these compounds, it can even be seen that the molecular structure is superior to the reference compound in terms of biological activity.

  The present invention will be further described with respect to particular embodiments and not by way of limitation of the invention (but only by the claims). Where the term “comprising” is used in the present description and claims, it does not exclude other aspects or steps. When a single noun is used, such as an indefinite article or definite article referring to “a” or “an”, “the”, this means that a plurality of nouns, unless specifically stated otherwise. Include.

  The term “prodrug” as used throughout this specification refers to a pharmacologically acceptable derivative, eg, the product resulting from biotransformation of the derivative is defined in the compound of formula (I). By ester or amide, such as an active agent. Goodman and Gilman, generally describing prodrugs, the Pharmaceutical Basis of Therapeutics, 8th ed. McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. The contents of 13-15 are incorporated herein. Prodrugs are characterized by good water solubility and bioavailability and are easily metabolized in vivo to active inhibitors.

C ₁ -C ₆ alkyl as used herein as a group or part of a group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1- Defined as methylethyl, butyl, pentyl, hexyl, 2-methylbutyl, and the like.

_C 1 _{-C 10} alkyl as part of or groups as groups, linear or saturated hydrocarbon group branched chain, for _example, the groups defined for C 1 -C ₆ alkyl having 1 to 10 carbon atoms, and heptyl , Octyl, nonyl, 2-methylhexyl, 2-methylpeptyl, decyl, 2-methylnonyl, and the like. Optionally, C ₁ -C ₁₀ alkyl, cycloalkyl moiety, preferably may encompass cyclopropyl moiety, for example, can methylcyclopropyl, ethylcyclopropyl, and the like.

The term “C ₂ -C ₁₀ alkenyl” as used herein as a group or part of a group refers to a straight chain having at least one double bond, preferably one double bond, and 2 to 10 carbon atoms. Having a chain or branched chain unsaturated hydrocarbon group, such as ethenyl, propenyl, buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, Hexen-1-yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-1-yl, hepten-1-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, 2-methylhexen-1-yl, octen-1-yl, octen-2-yl, octen-3-ylocten-4-yl, 2-methylhepten-1-yl, nonen-1-yl, nonen-2 -Ile Nonen-3-yl, nonen-4-yl, nonen-5-yl, 2-methylocten-1-yl, decene-1-yl, decene-2-yl, decene-3-yl, decene-4-yl , Decene-5-yl, 2-methylnonen-1-yl, and the like.

If C ₂ -C ₁₀ alkenyl group is bonded to a heteroatom, preferably, bonded via a saturated carbon atom.

C ₁ -C ₆ alkoxy as a group or part of a group is O—C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ alkyl independently has the meaning provided above.

C ₃ -C ₇ cycloalkyl, cyclopropyl, it is a generic term for cyclobutyl, cyclopentyl, the cyclohexyl or cycloheptyl.

As used herein, the term-(CR ₇ R ₈ ) _n is defined as n repetitions of subgroup CR ₇ R ₈ , and each of these subgroups is defined independently.

  Halogen is a generic term for fluoro, chloro, bromo and iodo.

  It should be noted that the position of the group on any molecular moiety used in the above definition can be anywhere on such moiety as long as it is chemically stable.

  The groups used in the above definition of variable include all possible isomers unless otherwise specified. For example, pentyl includes 1-pentyl, 2-pentyl and 3-pentyl. Each definition is independent if any change occurs more than once in any configuration.

  As used below, the term “compound of formula (I)” or “compound of the invention” or similar terms refers to compounds of general formula (I), their prodrugs, N-oxides, addition salts, quaternary It is meant to encompass amines, metal complexes and stereochemical isomer forms.

  Some of the compounds of formula (I) may be recognized as containing stereochemical isomers containing one or more chiral centers.

  As used herein, the term “stereochemical isomer form” is composed of multiple atoms joined by the same stretch of bonds, but has a different three-dimensional structure that cannot be interconverted and has the formula (I) Is defined as all possible compounds that can be possessed by

  Unless otherwise stated or indicated, the chemical name of a compound includes a mixture of all possible stereochemical isomeric forms that the compound may have. The mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of the compound. All stereochemical isomers of the compounds of the present invention are intended to be included within the scope of the present invention, both in pure form and in the form of mixtures with one another.

  The stereochemically pure forms of the compounds and intermediates described herein are isomeric substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compounds or intermediates. Define the body. In particular, the term “stereoisomerically pure” refers to at least 80% stereoisomer excess (ie, a minimum of 90% of one isomer and a maximum of 10% of other possible isomers) to 100% of stereoisomerism. A compound or intermediate having up to 100% excess (ie, 100% of one isomer and no other isomer), more particularly having a stereoisomeric excess of 90% to 100%, even more particularly It relates to compounds or intermediates having a stereoisomer excess from 94% to 100%, most particularly having a stereoisomer excess from 97% to 100%. The terms “pure enantiomer” and “pure diastereomer” should be understood in a similar sense, but on the one hand taking into account the enantiomeric excess, diastereomeric excess, respectively, of the mixture in question .

Pure stereoisomeric forms of the compounds and intermediates of the invention can be obtained by methods known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomers and optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. The pure stereochemically isomeric form can also be derived from the corresponding pure stereochemically isomeric form of the appropriate starting material, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound can be synthesized by a stereospecific production method. These methods advantageously use enantiomerically pure starting materials.

  The diastereomeric racemic compound of the formula (I) can be obtained by separation by a conventional method. Suitable physical separation methods that can advantageously be used are, for example, selective crystallization and chromatography (eg column chromatography).

  Absolute forms of compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines, or metal complexes, and some of the intermediates used in their preparation Has not been determined experimentally. One skilled in the art can determine the absolute form of such compounds using methods known in the art, such as X-ray diffraction.

  The present invention is also intended to include all isotopes of atoms present on the present compounds. Isotopes include those atoms having the same number of atoms but different mass numbers. By way of non-limiting general example, hydrogen isotopes include tritium and deuterium. Carbon isotopes include C-13 and C-14.

  For therapeutic applications, the salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, it has also been found that acid and base salts which are not pharmaceutically acceptable can be used, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

  The above pharmaceutically acceptable acid and base addition salts are meant to include the therapeutically effective, non-toxic acid and base addition salt forms from which the compounds of formula (I) can be produced. Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acid (eg, hydrochloric acid, hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, or, for example, acetic acid, propionic acid, hydroxyacetic acid, lactic acid, pyrubin Acid, succinic acid (ie ethanedioic acid), malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid (ie hydroxybutanedioic acid), tartaric acid, citric acid, methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

  The opposite form of the salt can be converted to the free base form by treatment with a suitable base.

  Acidic proton-containing compounds of formula (I) can also be converted to their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts (eg, lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc.) and organic bases (eg, benzathine salts, N -Methyl-D-glucamine salts, hydrabamine salts) and salts with amino acids such as arginine, lysine and the like.

  The term acid addition salt as used above also includes solvates from which compounds of formula (I) as well as their salts can be formed. Such solvates are, for example, hydrates, alcoholates, and the like.

As used above, the term quaternary amine means that the compound of formula (I) is substituted with the basic nitrogen of the compound of formula (I) and a suitable quaternizing agent (eg optionally substituted, It is defined as a quaternary ammonium salt that can be formed by a reaction between an alkyl halide, an aryl halide or an aralkyl halide, specifically methyl iodide or benzyl iodide. Other reactants having good leaving groups such as alkyl trifluoromethanesulfonate, alkyl methanesulfonate, alkyl p-toluenesulfonate, and the like can also be used. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counter ions include chlorine ions, bromine ions, iodine ions, trifluoroacetate ions and acetate ions. The selected counter ion can be introduced using an ion exchange resin.

  N-oxide forms of the compounds of the invention are meant to include compounds of formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxide.

  It is recognized that compounds of formula (I) can exist as metal complexes or metal chelates because they can have metal binding, chelating, and complex forming properties. Such metalated derivatives of compounds of formula (I) are intended to be included within the scope of the present invention.

  Also, some of the compounds of formula (I) may exist as tautomeric forms. Such forms cannot be specifically illustrated in the above formula, but are intended to be included within the scope of the present invention.

  The compounds of the present invention are recognized as having a wide variety of modifications with respect to the left and right portions of formula (I).

  While not detrimental to the full scope of the invention, certain embodiments are discussed in more detail below.

In a preferred embodiment, at most two X are N. In a preferred embodiment, one X is N. In a more preferred embodiment, one X is N and is in the meta position relative to the N—R ₂ group of the imidazole ring, and the N is in the ortho position relative to the ═N— atom of the imidazole ring.

In one preferred embodiment, R ₁ is selected from the group consisting of H, halogen and CH ₂ —NH ₂ . In a further preferred embodiment, R _{1 in the} para position to C—N—R ₂ is selected from the group consisting of H, halogen and CH ₂ —NH ₂ , and all other R ₁ are H. . In a further preferred embodiment, the halogen is bromo or chloro. In the most preferred embodiment, at most one R ₁ is chloro and all other R ₁ are H. In an even more preferred embodiment, R _{1 in the} para position relative to C—N—R ₂ is chloro.

In another preferred embodiment, R ₂ comprises a — (CR ₇ R ₈ ) n—R ₉ chain, and R ₇ and R ₈ are preferably H and n is 2-4. Preferably, R ₉ is OH, C ₁ -C ₆ alkyl (more preferably 2-propyl), C ₁ -C ₆ alkoxy (more preferably methoxy), SO ₂ R ₇ (R ₇ is preferably methyl) ). Most preferably R ₉ is fluoro or CF ₃ .

In a preferred embodiment, R ₃ is selected from the group consisting of C ₃ -C ₇ cycloalkyl (more preferably cyclopropyl) and a 4-membered saturated hydrocarbon containing one oxygen atom.

In preferred and more preferred embodiments in connection with other preferred embodiments, one Y is N and the other Y is C. In the most preferred embodiment, one Y is N in the para position relative to N—R ₃ .

Preferably at most one R ₄ is halogen, preferably fluoro. Most preferably, all of R ₄ are H.

  Preferred compounds are those listed below. More preferably, compound numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 16, 17, 18, 19, 20, 21, 31, 32, 33, 34, 35, And 36. Most preferred are compound numbers 1, 2, 16, 31, 32 and 33.

  Compounds of formula I can be prepared by synthetic methods known in the art of organic chemistry or by methods described below using modifications and derivatization methods familiar to those skilled in the art. The starting materials used here are either commercially available or can be prepared by conventional methods known in the art, such as those described in standard reference books. Although not limited, preferred methods include the following methods.

  Through all of the synthetic procedures described below, it may be necessary and / or desirable to protect sensitive or reactive groups on related molecules. This can be accomplished using conventional protecting groups such as T.I. W. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which is incorporated by reference, the contents of which are incorporated herein by reference.

  Compounds of formula I or their pharmaceutically acceptable salts can be prepared according to the reaction schemes herein below. Unless otherwise indicated, the substituents in the reaction scheme are as defined above. Product separation and purification can be accomplished by standard methods known to chemists of ordinary skill.

Scheme 1 illustrates a method for the preparation of compounds of formula I wherein R _{1 to} R ₄ and Y are as defined above.

Referring to Scheme 1, compounds of Formula I are prepared in methods known in the art such as the Mitsunobu reaction using azadiisopropyldicarboxylate and triphenylphosphine in a suitable solvent such as DMF or THF. , 2-hydroxymethylene imidazopyridine II-a and ^{N 3} - substituted 2-oxo - imidazo pyridine or ^{N 3} - substituted 2-oxo - can be synthesized by coupling of imidazo benzene III. Alternatively, the compound of formula I is a halide, preferably chlorinated II-b or in the presence of a base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as DMF or THF. It can be prepared by substitution of Z, which is a sulfonated product, preferably mesylate II-c.

Preparation of Compounds Il-b and II-c Alcohol II-a is treated with thionyl chloride to provide 2-chloromethylimidazopyridine II-b. Alternatively, alcohol II-a can be converted to intermediate II-c by reaction with methanesulfonyl chloride in the presence of an organic base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane (Scheme 2).

Preparation of Compound II-a The compound of Formula II-a is commercially available or can be prepared by the general method illustrated in Scheme 3 without limitation. Here, R ₁ , R ₂ and X are defined as described above. Referring to Scheme 3 below, haloheteroaryl IV (wherein W is a halogen, preferably fluorine) is reacted with ethanol or a primary amine of formula V at a reaction temperature from room temperature to 100 ° C. Treatment in a suitable solvent such as dichloromethane in the presence of a suitable base such as potassium carbonate can provide a compound of formula VI. Hydrogenation of the nitro group using well known conventional conditions such as Pd / C or other catalysts under hydrogen or Fe / EtOH / CaCl ₂ can provide the diamine of formula VII. Alternatively, hydrogenation of the nitro group of compound VIII using well known conventional conditions such as Pd / C or other catalysts under hydrogen or Fe / EtOH / CaCl ₂ gives a diamine of formula IX The diamine is treated with an aldehyde of formula X in a solvent such as methylene chloride, DMF or THF at about room temperature in the presence of a suitable reducing agent such as NaBH (OAc) ₃ or Na (CN) BH _3. Can provide a compound of formula VII. The imidazole ring can be formed by treating diamine VII with glycolic acid or ester-like XIII under strongly acidic conditions (eg, aqueous hydrochloric acid) and heating at reflux, to provide an alcohol of formula II-a. Alternatively, diamine VII can be condensed with a dialkoxyacetate of formula XII in the presence of acetic acid in a suitable solvent such as methanol to provide acetal II-e. The acetal of compound II-e can be eliminated with an acid such as hydrochloric acid to provide an aldehyde of formula II-f. The resulting aldehyde of formula II-f can be reduced with a suitable reducing agent such as NaBH ₄ or LiAlH _{4 in} a suitable solvent such as ethanol or THP to give the desired alcohol of formula II-a. it can. In addition, diamine VII can be cyclized with dialkyl oxalate of formula XI in a suitable solvent such as ethanol, with or without microwave heating, to produce an imidazole of formula II-d. Alternatively, compounds of formula II-d can be produced by a two-step synthesis starting from diamine VII. First, diamine VII is reacted with an alkyl trihaloacetimidate, preferably methyl 2,2,2-trichloroacetimidate, in an acid medium, preferably acetic acid, at a temperature in the range of 25-50 ° C. The compound of II-g can be obtained.
Second, reaction of a metal carbonate, preferably sodium carbonate, with a compound of formula II-g in a suitable solvent such as methanol results in a compound of formula II-d. Compound II-d can subsequently be reduced to the desired alcohol of formula II-a using a suitable solvent such as ethanol or THP.

  Another route for preparing Type II-a compounds is illustrated in Scheme 4. First, diamine IX can be coupled with alkyl glycolate or ester-like XIII under strongly acidic conditions such as aqueous hydrochloric acid under heating such as reflux to give an alcohol of formula XIV. This alcohol can be protected by PG to give compound XV, where PG is a protecting group such as, but not limited to, trityl. A suitable solvent for this type of reaction is not limited, but can be dichloromethane. Treatment of compound XV with compound XVI in the presence of a base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as DMF or THF provides compound II-h (where LG Is a leaving group such as halogen, preferably bromine, or sulfonate). Although elimination of PG in compound II-h is not limited, compound II-a can be obtained in the presence of an acid such as hydrochloric acid in the presence of a solvent such as dioxane. it can.

Compound III can be synthesized using the procedure illustrated in Scheme 5. Of nitropyridine or nitroaryl XVII W (halogen, preferably fluorine, or alkoxy group, preferably methoxy) in a suitable solvent such as THF or DMF in the presence of an organic base such as triethylamine or diisopropylamine. Substitution with an amine provides compound XVII. Reduction of the nitro group to amine XIX can be accomplished by catalytic methods using hydrogen in the presence of a catalyst such as palladium or platinum in a suitable solvent such as methanol, or iron or concentrated hydrochloric acid in the presence of ammonium chloride. It can be carried out in a stoichiometric method using tin chloride in the presence. In a solvent such as acetonitrile or THF, CDI, phosgene, or triphosgene, cyclized obtained diamine XIX used is, ^{N 3} - substituted 2-oxo - imidazo pyridine or ^{N 3} - imidazo benzene III - substituted 2-oxo provide. Alternatively, type III compounds can be prepared via starting from commercially available dianiline XX [which can be cyclized by ring closure using CDI, phosgene or triphosgene] and then obtaining an intermediate of type XXI. Alkylation of the urea nitrogen of XXI can be achieved by a Mitsunobu reaction with a commercially available alcohol and by substitution of chlorine in a compound of type XXII to give a compound of formula III.

  A compound of formula (I) can be converted to the corresponding N-oxide form according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides (eg, sodium peroxide, potassium peroxide), and suitable organic peroxides include perbenzoic acid. Acid or halo-substituted perbenzoic acid (eg, 3-chloroperbenzoic acid), peroxoalkanoic acid (eg, peroxoacetic acid), alkyl hydroperoxide (eg, t-butyl hydroperoxide). Suitable solvents include, for example, water, lower alcohols (eg, ethanol, etc.), hydrocarbons (eg, toluene), ketones (eg, 2-butanone), halogenated hydrocarbons (eg, dichloromethane) and such solvents. It is a mixture.

  Pure stereochemically isomeric forms of the compounds of formula (I) can be obtained by applying methods known in the art. Diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques (eg, countercurrent distribution, liquid chromatography, etc.).

  The compounds of formula (I) prepared by the above method are generally racemic mixtures of enantiomers, which can be separated from each other according to separation methods known in the art. Racemic compounds of formula (I), which are fully bases or acids, can be converted into the corresponding diastereomeric salts with the appropriate chiral acid or chiral base, respectively. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. Alternative methods for separating enantiomeric forms of the compounds of formula (I) include liquid chromatography, particularly liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms described above can also be derived from the appropriate starting materials of the corresponding stereochemically isomeric forms provided that the reaction occurs stereochemically. is there. If a specific stereoisomer is desired, the compound is preferably synthesized by a stereospecific production method. These methods can advantageously use enantiomerically pure starting materials.

  In a further aspect, the invention provides therapeutically effective compounds of any of the embodiments of the compounds of formula (I) as specified herein or of the compounds of formula (I) as specified herein. And a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In this context, a therapeutically effective amount is used to prophylactically act against, or stabilize or reduce, a viral infection, particularly an RSV viral infection, in an infected patient or a patient at risk of infection. The amount is sufficient to cause In yet a further aspect, the invention relates to a method of preparing a pharmaceutical composition as specified herein, said method being as specified herein or a compound of formula (I) as specified herein. In some embodiments, the compound of formula (I) comprises intimately mixing a therapeutically effective amount of a compound of any of the embodiments and a pharmaceutically acceptable carrier.

Accordingly, the compounds of the present invention or any embodiment thereof can be formulated into various pharmaceutical dosage forms for administration purposes. Suitable compositions include all compositions commonly used for systemically administered drugs. In preparing the pharmaceutical compositions of the present invention, an effective amount of a particular compound, any acid addition salt form or metal complex as an active ingredient will depend on the form of preparation desired for administration. Formulated in intimate admixture with a pharmaceutically acceptable carrier that can take a wide variety of forms. These pharmaceutical compositions are preferably in a single dosage form suitable for administration by oral, rectal, transdermal, or parenteral injection. For example, in the preparation of compositions in oral dosage formulations, all conventional pharmaceutical media, oral liquid formulations such as suspensions, syrups, elixirs, emulsions and solutions include, for example, water, glycols, Solid carriers such as oils, alcohols, etc., or in the case of powders, pills, capsules and tablets, starches, sugars, kaolins, lubricants, binders, disintegrants, etc. can be used. Because of their ease of administration, it is clear that tablets and capsules represent the most advantageous oral dosage unit formulations, in which case solid pharmaceutical carriers are used. For parenteral compositions, the carrier is usually at least predominantly sterile water, but may contain other ingredients, for example, to enhance solubility. The injectable solution can be prepared, for example, in a physiological saline solution, a glucose solution, or a mixed solution of salt and glucose. Injectable suspensions may be prepared using appropriate liquid carriers, suspending agents and the like. Also included are solid formulations that are intended to be converted to liquid form preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier may contain a penetration enhancer and / or a suitable wetting agent, and in smaller proportions may be formulated with any suitable additive. Additives should not have a significant adverse effect on the skin.

  The compounds of the invention can be administered by oral inhalation or oral gas infusion and are administered by methods and formulations used in the art for administration via this mode. Thus, in general, the compounds of the present invention can be administered to the lung in the form of a liquid, suspension or dry powder, with liquid being preferred. Systems developed for the delivery of liquids, suspensions or dry powders by oral inhalation or oral gas infusion are suitable for the administration of the compounds of the invention.

  Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier adapted for administration by inhalation or insufflation through the mouth. Preferably, the compounds of the invention are administered via inhalation of a nebulized or aerosol dosage form solution.

  For ease of administration and uniformity of dosage, it is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage formulations. As used herein, a unit dosage formulation means a physically discrete unit suitable as a unitary dosage, each unit being calculated to be effective for the desired treatment with the required pharmaceutical carrier. Containing a predetermined amount of active ingredient. Examples of such unit dosage formulations are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, cachets, injectable solutions or suspensions, etc. , And their isolated multiple agents.

  The compounds of formula (I) exhibit antiviral properties. Viral infections that can be treated using the compounds and methods of the present invention include infections caused by ortho- and paramyxoviruses, particularly human and bovine respiratory syncytial virus (RSV). The majority of the compounds of the present invention are also active against mutants of RSV. In addition, many compounds of the present invention exhibit an advantageous pharmacokinetic profile, include acceptable half-life, AUC and peak values, and lack biological phenomena such as insufficiently early onset and tissue retention. Has attractive properties due to scientific availability.

  The in vitro antiviral activity of the compounds of the present invention against RSV is tested as described in the experimental part of the specification and is exemplified in a virus yield reduction assay. The in vivo anti-urus activity of the compounds of the present invention against RSV can be exemplified by a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31-42).

Due to their antiviral properties, in particular anti-RSV properties, compounds of formula (I) or any embodiment thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and steric Chemical isomer forms are useful for the treatment of those experiencing viral infections, particularly RSV infections, or for the prevention of these infections. In general, the compounds of the present invention may be useful in warm-blooded animals infected with viruses, particularly respiratory syncytial viruses.

  Accordingly, the compounds of the present invention or any aspect thereof are used as medicaments. Such use in a pharmaceutical or therapeutic method includes systemic administration in an amount effective to control a viral infection, particularly a condition associated with RSV infection, to a patient infected with or at risk of viral infection. Become.

  The present invention also relates to the use of the compounds of the invention or any embodiment thereof in the manufacture of a medicament for the treatment or prevention of viral infections, in particular RSV infections.

  The invention further relates to a method for the treatment of warm-blooded animals infected with a virus, in particular RSV, or at risk of infection with a virus, in particular RSV, which comprises a compound of formula (I) as specified herein. Or administering an antivirally effective amount of a compound of any embodiment of the compounds of formula (I) as specified herein.

  In general, the daily effective amount for antiviral effect is 0.01 mg to 500 mg, more preferably 0.1 mg to 50 mg per kg body weight. The required dose may be administered as 2, 3, 4 or more sub-doses at appropriate intervals throughout the day. The sub-dose can be formulated as a unit dosage formulation containing, for example, 1-1000 mg, particularly 5-200 mg of the active ingredient per unit dosage formulation.

  The exact dosage and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, age, weight, gender, disease and physical nature of the particular patient. Depends on the extent of the condition, as well as other medications known to those skilled in the art that the patient is taking. Furthermore, it is apparent that the effective daily dose can be reduced or increased depending on the response of the patient being treated and / or depending on the judgment of the physician prescribing the compound of the invention. Therefore, the above effective daily dose range is merely an indicator.

  Combinations of other antiviral agents and compounds of formula (I) can also be used as medicaments. Thus, the present invention also relates to products containing (a) a compound of formula (I) and (b) other antiviral agents as a combination formulation for simultaneous, separate or sequential use in antiviral treatment. . Different agents can be combined in a single formulation with a pharmaceutically acceptable carrier. For example, the compounds of the invention can be combined with interferon beta or tumor necrosis factor alpha to treat or prevent RSV infection.

  The present invention is specifically described below with reference to the following non-limiting examples.

Example 1
Synthesis of Intermediates All of the intermediates required for the synthesis of target compounds of Formula I are synthesized as described in Schemes 6-14 below.

Step 1: Synthesis of 3- (methylsulfonyl) propan-1-ol 6-b 3- (Methylthio) propan-1-ol 6-a (200 g, 1900 mmol, CAS 505-10-2) was converted to CH ₂ Cl ₂ ( 2000 mL). The mixture was cooled to 0 ° C. In water, 85% m-CPBA (970 g, 5700 mmol, CAS 937-14-4) was added dropwise while maintaining the temperature at 0-5 ° C. After the addition, the mixture was warmed to 25 ° C. and stirred for 15 hours. The reaction mixture was filtered through a celite pad. The filtrate was purified by flash column (eluent: petroleum ether: ethyl acetate = 3: 1, then ethyl acetate: methanol = 10: 1) to give intermediate 6-b (75 g, 29%).

Step 2: 1-Bromo-3- (methylsulfonyl) propan-6-c synthetic intermediate 6-b (75g, 543mmol) of was dissolved in _CH 2 _Cl 2 (750 mL). The mixture was cooled to 0 ° C. Phosphorus tribromide (53.6 mL, 570 mmol) was added dropwise while maintaining the temperature at 0-5 ° C. After the addition, the mixture was warmed to 25 ° C. and stirred for 15 hours. The reaction mixture was poured into ice water. The separated organic layer was washed with brine (2 × 500 mL), dried over Na ₂ SO ₄ , filtered and then evaporated under reduced pressure to give the title compound 6-c (77 g, 71%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 2.25-2.40 (m, 2H) 2.91 (s, 3H) 3.1-3.2 (m, 2H) 3.5-3.6 ( m, 2H).

Step 3: N-(diphenylmethylene) -3- (methylsulfonyl) propan - was dissolved in synthetic intermediate 6-c (27g, 134mmol) amine 6-d and _CH 3 CN (60 mL). Diphenylmethylamine (27 g, 148 mmol) and DIEA (19.6 g, 152 mmol) were added. The mixture was refluxed for 4 hours and then cooled to room temperature. The mixture was neutralized with 50% aqueous acetic acid at 25 ° C. Water (80 mL) was added. This mixture was extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and then evaporated under reduced pressure. The resulting residue was washed with petroleum ether (4 × 100 mL). The mixture was treated with methyl tert-butyl ether. The solid was collected and purified by column chromatography (eluent: CH ₂ Cl ₂ : ethyl acetate = 1: 0 to 10: 0). The title compound 6-d was obtained as a white solid (34 g, 85%).

Step 4: Synthesis of 3- (methylsulfonyl) propan-1-amine 6-e Intermediate 6-d (34 g, 113 mmol) was dissolved in dioxane (600 mL). The mixture was cooled to 0-5 ° C. and a solution of 4N HCl / dioxane (120 mL, 480 mmol) was added dropwise. After the addition, the mixture was warmed to 25 ° C. and stirred for 15 hours. This mixture was filtered. The solid was collected and washed with dioxane. The title product 6-e was obtained as a yellow powder (11.5 g, 50%)

4-Chlorobutan-1-ol 7-a (100 g, 920 mmol, CAS 928-51-8) was dissolved in CH ₂ Cl ₂ at room temperature. The mixture was cooled to 0 ° C. and then imidazole (81.5, 1200 mmol and TBDMS-C1 (152 g, 1010 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours and then filtered. Washed successively with 10% aqueous HCl and brine The resulting solution was dried over MgSO ₄ , filtered, and concentrated to give the title compound 7-b as a colorless oil (100 g, 50%).

CH ₂ Cl ₂ (1500mL) in 4-aminobutanol 8-a (50g, 561mmol, CAS 13325-10-5), imidazole (167g, 2450mmol) and tert- butylchlorodiphenylsilane (170g, 618mmol, CAS 58479- 61-1) was stirred for 15 hours at 25 ° C. The resulting mixture was washed successively with saturated NaHCO ₃ (2 × 800 mL), water (2 × 800 mL) and brine (2 × 500 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The product 8-b was obtained as an oil (200 g, 95%).

Step 1: Synthesis of 4- (methylthio) butan-1-ol 9-a 4-Chlorobutan-1-ol 7-a (180 g, 1658 mmol, CAS 928-51-8) was treated with sodium thio at 0-5 ° C. Added to methoxide (656 g, 1965 mmol, 21% solution in water). After the addition, the mixture was warmed to 25 ° C. and stirred for 48 hours. This mixture was extracted with CHCl ₃ . The separated organic layer was dried over Na ₂ CO ₃ , filtered and evaporated under reduced pressure. The residue was distilled (144.2 g, 72%) to provide alcohol 9-a as an oil.

Step 2: Synthesis of 4- (methylsulfonyl) butan-1-ol 9-b Intermediate 9-a (141 g, 1173 mmol) was dissolved in CH ₂ Cl ₂ (9000 mL). The mixture was cooled to 0-5 ° C. M-CPBA (483 g, purity 85%, 2375 mmol, CAS 937-14-4) was gradually added at 0-5 ° C. After the addition, the mixture was warmed to 25 ° C. and stirred for 15 hours. The mixture was filtered through a celite pad. The filtrate was purified by flash column (eluent: petroleum ether: ethyl acetate = 3: 1, then ethyl acetate: methanol = 10: 1). The product 9-b (98 g, 65%) was thus obtained.

Step 3: 1-bromo-4- (methylsulfonyl) butanoic 9-c of the synthetic intermediate 9-b (98g, 645mmol) _was dissolved in CH ₂ Cl ₂ (1100mL). The mixture was cooled to 0-5 ° C. PBr ₃ (64 mL, 674 mmol) was added dropwise at 0-5 ° C. After the addition, the mixture was warmed to 25 ° C. and stirred for 15 hours. The mixture was poured into ice water. The separated organic layer was washed with brine (2 × 500 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The product 9-c was obtained (84.5 g, 80%).

Step 1: Synthesis of N-cyclopropyl-3-nitropyridin-4-amine 10-b 4-methoxy-3-nitropyridine 10-a (200 g, 1300 mmol, CAS 31872-62-5) in dry ethanol (800 mL). ), Cyclopropylamine (185.5 g, 3250 mmol) and diisopropylethylamine (336 g, 2600 mmol) were refluxed for 3 hours. The mixture was cooled to 0 ° C. The solid was collected by filtration. The filter cake was washed with cold ethanol (150 mL). The solid was dried to give the title compound 10-b as a white powder (167 g, 72%).

Step 2: Synthesis of N ⁴ -cyclopropylpyridine-3,4-diamine 10-c Intermediate 10-b (167 g, 932 mmol) in ethanol (1400 mL) and wet 10% PD / C (34 g) as catalyst. And hydrogenated at 20 ° C. overnight. After consumption of H ₂ (3 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was washed with methyl tert butyl ether to give compound 10-c as a yellow powder (133 g, 95%).

Step 3: Synthesis of 1-cyclopropyl-1H-imidazole [4,5-c] pyridin-2 (3H) -one 10-d Carbonyldiimidazole (151.8 g, 936 mmol) was added to CH ₃ CN at 0 ° C. To the intermediate 10-c solution in (1800 mL). The reaction mixture was warmed to 10 ° C. and stirred for 1 hour. The solid was collected by filtration and washed with CH ₃ CN (200 mL) to give the title compound 10-d as a white powder (101 g, 65%).

  Compound 11-d was prepared in the same manner as Compound 10-d using 3-aminooxetane as a starting material.

Step 1: Synthesis of N-cyclopropyl-4-fluoro-2-nitroaniline 12-b 1,4-Difluoro-2-nitrobenzene 12-a (CAS 364-74-9) (15 g, 94.3 mmol) was converted to DMF. (500 mL). Cyclopropylamine (7 mL, 100 mmol) was added followed by triethylamine (30 mL, 217 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was poured into water, extracted with dichloromethane, dried over MgSO ₄ and concentrated. The orange solid was purified by column chromatography using dichloromethane and methanol to give intermediate 12-b (16 g, 86%) as an orange solid.
m / z = 197 (M + H) ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.63-0.68 (m, 2H), 0.88-0.95 (m, 2H), 2.54-2.55 (m, 1H), 7.27-7.34 (m, 2H), 7.84-7.90 (m, 1H), 7.93-8.02 (m, 1H).

Step 2: Synthesis of N ¹ -cyclopropyl-4-fluorobenzene-1,2-diamine 12-c Intermediate 12-d (16 g, 82 mmol) in ethanol (200 mL) was treated with 10% wet PD as catalyst. Hydrogenated with / C overnight at room temperature. After consumption of H ₂ (3 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was washed with ethanol to give compound 9-c as a white solid (12.8 g, 94%). m / z = 167 (M + H) ⁺ .

Step 3: Synthesis of 1-cyclopropyl-5-fluoro-1H-benzo [d] imidazol-2 (3H) -one 12-d Carbonyldiimidazole (13.15 g, 81 mmol) was added CH ₃ CN at 0 ° C. To a solution of intermediate 12-c (12.8 g, 77.3 mmol) in (150 mL). The reaction mixture was warmed to room temperature and stirred for 4 hours. After removal of the solvent, the residue was purified by column chromatography using CH ₂ Cl ₂ / methanol to give a light brown solid, which was triturated in diethyl ether as a white solid, compound 12-d (7. 4 g, 50%). m / z = 193 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.99-1.08 (m, 2H) 1.08-1.20 (m, 2H) 2.89 (m, 1H) 6.75-6.84 ( m, 1H) 6.87 (dd, J = 8.53, 2.51 Hz, 1H) 7.10 (dd, J = 8.53, 4.27 Hz, 1H) 10.33 (br.S., 1H) ).

  Compound 13-d was prepared in the same manner as compound 12-d using 2-fluoronitrobenzene 13-a as the starting material.

  Compound 14-d was prepared in the same manner as Compound 12-d using 2,2-dichloro-3-nitropyridine 14-a and isopropylamine as starting materials.

Example 2
3-((5-Chloro-1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c] pyridine-2 ( Synthesis of 3H) -one 1

Step 1: Synthesis of 6-chloropyridine-2,3-diamine 1-1

To a mixture of ethyl acetate (450 mL) and tert-butanol (50 mL) was added 6-chloro-3-nitropyridin-2-amine (CAS 27048-04-0) (15 g, 86.42 mmol), stannous chloride dehydrate ( CAS 10025-69-1) (97.5 g, 432.1 mmol) was added. The resulting mixture was stirred at 60 ° C. for 1 hour. Sodium borohydride (1.63 g, 43.21 mmol) was added and the mixture was further stirred at 60 ° C. for an additional 3 hours. The reaction mixture was cooled and extracted from ethyl acetate by rotary evaporator. The obtained residue was diluted with water (350 mL), and the pH was neutralized to 9 to 10 by adding an aqueous potassium carbonate solution. The resulting mixture was extracted with ethyl acetate (3 × 250 mL), dried over Na ₂ SO ₄ and evaporated. The residue was stirred in a mixture of EtOAc / heptane 1/1 for 72 hours. The precipitate was filtered and dried under reduced pressure for 2 hours. Intermediate 1-1 was collected as a greenish powder (9.32 g, 75%). m / z = 144 (M + H) ⁺ .

Step 2: 6-Chloro -N ³ - Synthesis of isopropyl-2,3-diamine 1-2

Intermediate 1-1 (5 g, 34.82 mmol) was dissolved in dichloromethane (200 mL) and acetic acid (20 drops) and 4-methylpentanal (3 g, 34.8 mmol, CAS 1119-16-0) were added. . The resulting mixture was stirred for 30 minutes and then sodium triacetoxyborohydride (22.14 g, 104.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and 50% Na ₂ CO ₃ solution was added dropwise until gas evolution ceased. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography using heptane / EtOAc to pure EtOAc. Compound 1-2 was collected as a white solid and dried in vacuo overnight (4.8 g, 65%). m / z = 214 (M + H) ⁺ .

Step 3: Synthesis of (5-chloro-1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methanol 1-3

A mixture of Intermediate 1-2 (4.8 g, 22.46 mmol) and 2-hydroxyacetic acid (4.27 g, 56.2 mmol) was stirred at 150 ° C. for 4 hours. The mixture was cooled to room temperature and treated with 3N hydrochloric acid with caution. The resulting mixture was basified with aqueous ammonia and extracted with CH ₂ Cl ₂ (300 mL). The organic layer was dried over MgSO ₄ and then evaporated to dryness. The residue was purified by column chromatography on silica using CH ₂ Cl ₂ to EtOAc. Product 1-3 was isolated as a brown solid (3.5 g, 61%).
m / z = 255 (M + H) ⁺

Step 4: 3-((5-Chloro-1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c] pyridine -2 (3H) -one Synthesis of 1

Intermediate 1-3 (0.29 g, 1.14 mmol), triphenylphosphine (0.33 g, 1.25 mmol) and pyridobenzimidazolone 10-d (0.22 g, 1.4 mmol) in dry THF (30 mL). 25 ml) was added dropwise DIAD (94%, 0.287 mL, 1.37 mmol) at room temperature. The reaction mixture was stirred overnight. After the reaction was complete, the mixture was concentrated to dryness and the residue was purified by column chromatography eluting with ethyl acetate / CH ₂ Cl ₂ then CH ₂ Cl ₂ / methanol to give the title compound 1 as a white solid. (233 mg, 50%) was obtained. m / z = 412 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.95-1.06 (m, 2H), 0.99 (d, J = 6.5 Hz, 6H), 1.17 (m, 2H), 1 .52 (m, 1H), 1.64-1.76 (m, 2H), 2.85-2.96 (m, 1H), 4.30-4.41 (m, 2H), 5.37 (S, 2H), 7.13 (d, J = 5.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H) , 8.35 (d, J = 5.3 Hz, 1H), 8.69 (s, 1H)

Example 3
3-((5-Chloro-1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetan-3-yl) -1H-imidazo [4,5-c Synthesis of pyridin-2 (3H) -one 2

Compound 2 was prepared in the same manner as Compound 1 using Intermediates 1-3 and 11-d as starting materials. m / z = 428 (M + H) ^<+> .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.99 (d, J = 6.8 Hz, 6H), 1.51-1.61 (m, 2H), 1.70 (m, 1H), 4 .29-4.41 (m, 2H), 5.07-5.18 (m, 4H), 5.40 (s, 2H), 5.56-5.67 (m, 1H), 7.20 (D, J = 8.3 Hz, 1H), 7.58 (dd, J = 5.4, 0.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 8.41 ( d, J = 5.3 Hz, 1H), 8.75 (s, 1H)

Example 4
3-((5-Chloro-1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-5-fluoro-1H-benzo [d] imidazole-2 ( Synthesis of 3H) -one 6

Compound 6 was prepared in the same manner as Compound 1 using Intermediates 1-3 and 12-d as starting materials. m / z = 429 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.95-1.03 (m, 2H), 0.98 (d, J = 6.5 Hz, 6H), 1.09-1.17 (m, 2H), 1.45-1.54 (m, 2H), 1.65-1.69 (m, 1H), 2.84-2.89 (m, 1H), 4.34-4.42 ( m, 2H), 5.32 (s, 2H), 6.78 (ddd, J = 9.5, 8.7, 2.4 Hz, 1H), 7.07 (dd, J = 8.7, 4 .4 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.59 (d, J = 8. 5Hz, 1H)

Example 5
3-((5-Chloro-1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -3-cyclopropyl-1H-benzo [d] imidazol-2 (3H) -one Synthesis of 13

Compound 13 was prepared in the same manner as Compound 1 using Intermediates 1-3 and 13-d as starting materials. m / z = 411 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.97 (d, J = 6.8 Hz, 6H), 0.99-1.05 (m, 2H), 1.10-1.17 (m, 2H), 1.41-1.51 (m, 2H), 1.63-1.73 (m, 1H), 2.84-2.92 (m, 1H), 4.32-4.41 ( m, 2H), 5.37 (s, 2H), 7.01-7.12 (m.2H), 7.16-7.20 (m, 1H), 7.22 (d, J = 8. 3Hz, 1H), 7.51-7.55 (m, 1H), 7.58 (d, J = 8.5Hz, 1H)

Example 6
4- (5-Chloro-2-((1-cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -1H-imidazo [4,5- b] Synthesis of pyridin-1-yl) butyl pivalate 3

Step 1: Synthesis of (5-chloro-1H-imidazo [4,5-b] pyridin-2-yl) methanol 3-1.

A mixture of Intermediate 1-1 (14.5 g, 101 mmol) and 2-hydroxyacetic acid (16 g, 210 mmol) was stirred at 150 ° C. for 4 hours. The resulting mixture was cooled to 60 ° C., treated with 3N aqueous HCl (70 mL), and then made basic with pH 7-8 by adding aqueous ammonia. The mixture was filtered and the solid was collected and washed with water and methyl ter-butyl ether. Product 3-1 was collected as a yellow powder (17.5 g, 94%). m / z = 184 (M + H) ⁺ .

Step 2: Synthesis of 5-chloro-2- (trityloxymethyl) -1H-imidazo [4,5-b] pyridine 3-2

Intermediate 3-1 (17.5 g, 95.3 mmol) and triethylamine (28 mL, 190.6 mmol) were dissolved in dichloromethane (300 mL). Then, 40 g of trityl chloride (143 mmol) was added. The resulting mixture was stirred for 1.5 hours at 25 ° C. The reaction mixture was washed with 1N aqueous hydrochloric acid and filtered. The solid was collected and washed with dichloromethane (500 mL). The filtrate was washed with 1N aqueous hydrochloric acid (200 mL) and then with saturated aqueous NaHCO ₃ (200 mL). The organic layer was dried over Na ₂ SO ₄ and evaporated under vacuum until almost dry. The residue was filtered. The solid was collected and washed with dichloromethane. The product 3-2 was collected (27 g, 68%). m / z = 426 (M + H) ⁺ .

Step 3: Synthesis of 4- (5-chloro-2- (trityloxymethyl) -1H-imidazo [4,5-b] pyridin-1-yl) butyl pivalate 3-3

To intermediate 3-2 (27 g, 63.4 mmol) and 4-chlorobutyl pivalate (19 g, 83.8 mmol), cesium carbonate (40 g, 122 mmol) and potassium iodide (3 g, 18 mmol) were added. The mixture was dissolved in DMF at 25 ° C., then warmed to 80 ° C. and stirred for 2 hours. The reaction mixture was cooled to 25 ° C., filtered, and the filtrate was poured into ice-water. The mixture was extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by chromatography (eluent: ethyl acetate: petroleum ether = 1: 3). Two isomers were collected, compound 3-3 (5 g) and compound 3-4 (20 g). m / z = 582 (M + H) ⁺ .

Step 4: Synthesis of 4- (5-chloro-2- (hydroxymethyl) -1H-imidazo [4,5-b] pyridin-1-yl) butyl pivalate 3-5

Intermediate 3-3 _(5g, 8.6mmol), was dissolved in CH ₂ Cl ₂ (50mL). 4N HCl / dioxane solution (20 mL, 80 mmol) was added at 0 ° C. The mixture was stirred for 2 hours at 25 ° C. The reaction mixture was evaporated at 40-45 ° C. under reduced pressure. The residue was co-evaporated with CH ₂ Cl ₂ (70 mL). To this residue was added dichloromethane (70 mL). The mixture was filtered and the solid was collected and washed with methyl tert-butyl ether. The hydrochloride salt of product 3-5 was collected as a white powder (2.83 g, 86%). This powder was dissolved in a mixture of water (50 mL) and dichloromethane (50 mL). Sodium bicarbonate (1.02 g, 12 mmol) was then added in portions at 25 ° C. and the mixture was stirred at 25 ° C. overnight. The resulting mixture was extracted with dichloromethane, dried over MgSO ₄ and concentrated. Product 3-5 was collected as a white solid. m / z = 340 (M + H) ⁺ .

Step 5: 4- (5-Chloro-2- (1-cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -1H-imidazo [4 Synthesis of 5-b] pyridin-1-yl) butyl pivalate 3

Stirring of intermediate 3-5 (0.4 g, 1.16 mmol), triphenylphosphine (0.35 g, 1.34 mmol) and compound 10-d (0.214 g, 1.22 mmol) in dry THF (30 mL) To the solution was added DIAD (94%, 0.264 mL, 1.34 mmol) dropwise at room temperature. The reaction mixture was stirred overnight. After the reaction was complete, the mixture was concentrated to dryness and the residue was purified by column chromatography eluting with ethyl acetate / CH ₂ Cl ₂ then CH ₂ Cl ₂ / methanol to give the title compound as a white solid 3 was obtained (360 mg, 60%).
m / z = 498 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.97-1.04 (m, 2H), 1.13-1.20 (m, 11H), 1.66-1.85 (m, 4H) , 2.92 (tdd, J = 6.9, 6.9, 3.8, 3.5 Hz, 1H), 4.08 (t, J = 6.1 Hz, 2H), 4.43 (t, J = 7.3 Hz, 2H), 5.38 (s, 2H), 7.13 (d, J = 6.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.64 (D, J = 8.5 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.75 (Dd, J = 0.5 Hz, 1H)

Example 7
3-((5-Chloro-1- (4-hydroxybutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c Synthesis of pyridin-2 (3H) -one 14

Compound 3 (0.29 g, 0.58 mmol) was dissolved in THF (15 mL), and hydroxylithium (40 mg, 1.6 mmol) was dissolved in water (5 mL) and added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography using dichloromethane and methanol to give the title compound 14 (200 mg, 80%) as a white powder. m / z = 414 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.94 (m, J = 2.8 Hz, 2H), 1.09 (m, J = 5.3 Hz, 2H), 1.39-1.51 (M, 2H), 1.73 (quin, J = 7.6 Hz, 2H), 3.01 (tt, J = 6.9, 3.5 Hz, 1H), 3.39-3.45 (m, 2H), 4.41 (t, J = 7.4 Hz, 2H), 5.47 (s, 2H), 7.31 (d, J = 5.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H).

Example 8
1-cyclopropyl-3-((1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-benzo [d] imidazol-2 (3H) -one Composition

Step 1: Synthesis of (1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methanol 4-3

  Intermediate 4-3 was prepared in the same manner as Intermediate 1-3 using pyridine-2,3-diamine 4-1 as the starting material.

Step 2: 1-cyclopropyl-3-((1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-benzo [d] imidazol-2 (3H)- Synthesis of On 4 Compound 4 was prepared in the same manner as Compound 1 using Intermediates 4-3 and 13-d as starting materials.
m / z = 376 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.96 (d, J = 6.5 Hz, 6H), 0.99-1.06 (m, 2H), 1.10-1.19 (m, 2H), 1.37-1.51 (m, 2H), 1.69 (dquin, J = 13.3, 6.7, 6.7, 6.7, 6.7 Hz, 1H), 2.89. (Tt, J = 6.9, 3.5 Hz, 1H), 4.26-4.44 (m, 2H), 5.40 (s, 2H), 7.06 (m, J = 8.8, 7.5, 1.3 Hz, 2H), 7.14-7.23 (m, 2H), 7.54 (dd, J = 7.3, 1.3 Hz, 1H), 7.62 (dd, J = 8.0, 1.5 Hz, 1H), 8.54 (dd, J = 4.8, 1.3 Hz, 1H)

Example 9
1-cyclopropyl-3-((1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridin-2 (3H) -one Synthesis of 5

Compound 5 was prepared similarly to compound 4 using intermediate 10-d as starting material.
m / z = 377 (M + H) ⁺ .
¹ H NMR (360 MHz, chloroform-d) δ ppm 1.01 (m, 2H), 0.99 (d, J = 6.6 Hz, 6H), 1.13-1.21 (m, 2H), 1 .44-1.56 (m, 2H), 1.62-1.77 (m, 1H), 2.87-2.96 (m, 1H), 4.30-4.40 (m, 2H) , 5.41 (s, 2H), 7.13 (d, J = 5.5 Hz, 1H), 7.21 (dd, J = 8.1, 4.8 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H)

Example 10
1-cyclopropyl-5-fluoro-3-((1-isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-benzo [d] imidazol-2 (3H) -one Synthesis of 8

Compound 8 was prepared similarly to compound 4 using intermediate 12-d as starting material.
m / z = 394 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.97 (d, J = 6.8 Hz, 6H), 0.99-1.04 (m, 2H), 1.08-1.18 (m, 2H), 1.39-1.56 (m, 2H), 1.60-1.74 (m, 1H), 2.77-2.97 (m, 1H), 4.25-4.46 ( m, 2H), 5.35 (s, 2H), 6.78 (m, J = 9.0, 2.0 Hz, 1H), 7.07 (dd, J = 8.7, 4.4 Hz, 1H) ), 7.20 (dd, J = 8.3, 4.8 Hz, 1H), 7.34 (dd, J = 8.4, 2.4 Hz, 1H), 7.64 (dd, J = 8. 0, 1.5 Hz, 1 H), 8.55 (dd, J = 4.8, 1.5 Hz, 1 H)

Example 11
3-((1-Isopentyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetan-3-yl) -1H-imidazo [4,5-c] pyridine-2 Synthesis of (3H) -one 9

Compound 9 was prepared similarly to compound 4 using intermediate 11-d as starting material.
m / z = 393 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.98 (d, J = 6.8 Hz, 6H), 1.48-1.59 (m, 2H), 1.62-1.77 (m, 1H), 4.26-4.39 (m, 2H), 5.06-5.19 (m, 4H), 5.43 (s, 2H), 5.58-5.69 (m, 1H) , 7.21 (dd, J = 8.3, 4.8 Hz, 1H), 7.58 (d, J = 5.3 Hz, 1H), 7.65 (dd, J = 8.0, 1.5 Hz) , 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.55 (dd, J = 4.8, 1.5 Hz, 1H), 8.81 (s, 1H).

Example 12
1-cyclopropyl-3-((1- (3-methylsulfonyl) propyl-1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridine- Synthesis of 2 (3H) -one 7

Step 1: Synthesis of N- (3-methylsulfonyl) propyl) -2-nitropyridin-3-amine 7-1

3-Fluoro-2-nitropyridine (0.7 g, 4.92 mmol, CAS 54231-35-5) was dissolved in DMF (30 mL). Then 3- (methylsulfonyl) propan-1-amine hydrochloride 6-e (0.9, 5.2 mmol) was added followed by triethylamine (1.5 mL, 11.3 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was poured into water, extracted with dichloromethane, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography using ethyl acetate to give intermediate 7-1 as an orange solid (1.2 g, 93%).
m / z = 260 (M + H) ⁺ .

Synthesis of (3-methylsulfonyl) propyl) pyridine-2,3-diamine 7-2 - N ^3: Step ²

Intermediate 7-1 (1.2 g, 4.62 mmol) was hydrogenated in THF (300 mL) at 20 ° C. using wet 10% Pd / C (0.5 g) as a catalyst. After consumption of H ₂ (3 eq), the catalyst was filtered off and the filtrate was then evaporated. The residue was washed with methyl ter-butyl ether to give the title compound 7-2 as a pale yellow powder (1 g, 94%). m / z = 230 (M + H) ⁺ .

Step 3: Synthesis of (1- (3- (methylsulfonyl) propyl) -1H-imidazo [4,5-b] pyridin-2-yl) methanol 7-3

A mixture of Intermediate 7-2 (1 g, 4.36 mmol) and methyl 2-hydroxyacetate (2 mL, 26 mmol) was stirred at 130 ° C. overnight. The resulting mixture was cooled to room temperature and diluted with dichloromethane. The obtained future product was poured into water and extracted with dichloromethane. The organic layer was dried over MgSO ₄ and concentrated. After evaporation of the aqueous layer, both residues were mixed and purified by column chromatography using dichloromethane / methanol. Product 7-3 was collected as a white powder (0.43 g, 36%). m / z = 270 (M + H) ⁺ .

Step 4: 1-cyclopropyl-3-((1- (3-methylsulfonyl) propyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5- c] Synthesis of Pyridin-2 (3H) -one 7 Compound 7 was prepared in the same manner as Compound 1 using Intermediates 7-3 and 10-d as starting materials.
m / z = 427 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.89-0.97 (m, 2H), 1.03-1.12 (m, 2H), 2.10-2.25 (m, 2H) ), 3.00 (s, 3H), 2.93-3.05 (m, 1H), 3.19-3.27 (m, 2H), 4.52 (t, J = 7.4 Hz, 2H) ), 5.48 (s, 2H), 7.29 (m, J = 5.0 Hz, 2H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 8.27 (d , J = 5.3 Hz, 1H), 8.38 (dd, J = 4.8, 1.5 Hz, 1H), 8.45 (s, 1H)

Example 13
1-cyclopropyl-3-((1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridine-2 Synthesis of (3H) -one 10

Synthesis of (3-methoxypropyl) pyridine-2,3-diamine 10-2 - N ^3: Step ¹

  Intermediate 10-2 was prepared in the same manner as Intermediate 7-2 using 3-methoxypropan-1-amine as the starting material.

Step 2: Synthesis of 2- (diethoxymethyl) -1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridine 10-3

Intermediate 10-2 (10 g, 34.43 mmol) was dissolved in ethanol (70 mL). Then ethyl 2,2-diethoxyacetate (7.39 mL, 41.3 mmol) and sodium ethanolate (14.14 mL, 37.8 mmol) were added. The resulting mixture was refluxed for 4 days. The dark solution was cooled to room temperature and then the solvent was removed under reduced pressure. The residue was dissolved in water (300 mL) and dichloromethane was added. The mixture was extracted with dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography eluting with ethyl acetate / dichloromethane. Intermediate 10-3 was collected (5.15 g, 48%). m / z = 294 (M + H) ⁺ .

Step 3: Synthesis of 1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridine-2-carbaldehyde 10-4

Intermediate 10-3 (5.15 g, 17) in 1N aqueous hydrochloric acid (79 mL, 79 mmol).
. 55 mmol) was stirred at 60 ° C. for 2 days. The resulting mixture was allowed to cool to room temperature and then ethyl acetate and water were added. The pH was adjusted to basic by adding a saturated solution of Na ₂ CO ₃ and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. Compound 10-4 was collected as a dark brown oil (3 g, 76%).

Step 4: Synthesis of 1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridin-2-yl) methanol 10-5

To a solution of intermediate 10-4 (3 g, 10.4 mmol) in THF (40 mL) and methanol (40 mL) was slowly added sodium borohydride (0.8 g, 21 mmol) at 0 ° C. The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue was then dissolved in ethyl acetate (50 mL) and water was added (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The separated organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography using dichloromethane / methanol. The title compound was collected as an orange oil (1 g, 42%). m / z = 222 (M + H) ⁺ .

Step 5: 1-cyclopropyl-3-((1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] Synthesis of Pyridin-2 (3H) -one 10 Compound 10 was prepared similarly to Compound 1 using Intermediates 10-5 and 10-d as starting materials. m / z = 379 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88-0.97 (m, 2H), 1.03-1.14 (m, 2H), 1.99 (quin, J = 6.3 Hz) , 2H), 3.00 (tt, J = 6.8, 3.6 Hz, 1H), 3.23 (s, 3H), 3.29 (t, J = 5.9 Hz, 2H), 4.44 (T, J = 6.8 Hz, 2H), 5.46 (s, 2H), 7.26 (dd, J = 8.0, 4.8 Hz, 1H), 7.30 (d, J = 5. 3 Hz, 1 H), 7.97-8.06 (m, 1 H), 8.27 (d, J = 5.3 Hz, 1 H), 8.33-8.39 (m, 1 H), 8.41 ( s, 1H).

Example 14
3-((1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetan-3-yl) -1H-imidazo [4,5- c] Synthesis of Pyridin-2 (3H) -one 12

Compound 12 was prepared in the same manner as compound 10 using intermediate 11-d as starting material. m / z = 395 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.01 (quin, J = 6.3 Hz, 2H), 3.23 (s, 3H), 3.30 (t, J = 1.0 Hz, 2H ), 4.45 (t, J = 6.9 Hz, 2H), 4.93-5.04 (m, 2H), 5.09 (t, J = 6.7 Hz, 2H), 5.50 (s) , 2H), 5.53-5.64 (m, 1H), 7.26 (dd, J = 8.0, 4.8 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H) 8.02 (dd, J = 8.0, 1.3 Hz, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.36 (dd, J = 4.8, 1.3 Hz) , 1H), 8.50 (s, 1H).

Example 15
1-cyclopropyl-5-fluoro-3-((1- (3-methoxypropyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-benzo [d] imidazole-2 Synthesis of (3H) -one 15

Compound 15 was prepared similarly to compound 10 using intermediate 12-d as starting material. m / z = 396 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.84-0.95 (m, 2H), 1.01-1.13 (m, 2H), 1.97 (m, J = 6.3) , 6.3, 6.3, 6.3 Hz, 2H), 2.94 (m, J = 6.8, 6.8, 3.5, 3.5 Hz, 1H), 3.23 (s, 3H) ), 3.25-3.29 (m, 2H), 4.43 (t, J = 6.9 Hz, 2H), 5.38 (s, 2H), 6.84-6.99 (m, 1H) ), 7.17 (dd, J = 9.2, 2.4 Hz, 1H), 7.22 (dd, J = 1.0 Hz, 1H), 7.26 (dd, J = 1.0 Hz, 1H) , 8.00 (dd, J = 8.0, 1.3 Hz, 1H), 8.36 (dd, J = 4.5, 1.3 Hz, 1H).

Example 16
1-cyclopropyl-3-((1- (3-fluoropropyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridine-2 Synthesis of (3H) -one 11

Intermediate 11-5 was prepared by using 3-fluoropropan-1-amine hydrochloride (CAS
Prepared analogously to Intermediate 10-5 using 64068-31-1) and 3-fluoro-2-nitropyrimidine (CAS 54231-35-35).

Compound 11 was prepared in the same manner as compound 10 using intermediates 11-5 and 10-d as starting materials. m / z = 337 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88-0.97 (m, 2H), 1.02-1.11 (m, 2H), 2.06-2.26 (m, 2H) ), 3.00 (dt, J = 6.9, 3.3 Hz, 1H), 4.39-4.63 (m, 4H), 5.46 (s, 2H), 7.27 (dd, J = 8.2, 4.6 Hz, 1H), 7.30 (d, J = 5.3 Hz, 1H), 8.04 (dd, J = 8.0, 1.5 Hz, 1H), 8.27 ( d, J = 5.3 Hz, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 8.41 (s, 1H).

Example 17
3-((6-Bromo-3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c] pyridine-2 ( Synthesis of 3H) -one 16

Intermediate 16-5 was prepared by using 5-bromo-2-chloro-3-nitropyrimidine (
Prepared according to the 5-step synthesis described for Intermediate 10-5 using CAS 67443-38-3) and 3-methylbutane-1-amine (CAS 107-85-7).

Compound 16 was prepared similarly to compound 10 using intermediates 16-5 and 10-d as starting materials. m / z = 456 (M + H) ⁺ .
¹ H NMR (360 MHz, chloroform-d) δ ppm 0.97 (d, J = 6.6 Hz, 6H), 0.99-1.07 (m, 2H), 1.18-1.21 (m, 2H), 1.54-1.62 (m, 2H), 1.68 (tt, J = 13.3, 6.6 Hz, 1H), 2.93 (tdd, J = 6.9, 6.9). , 3.7, 3.5 Hz, 1H), 4.39 (m, J = 8.1 Hz, 2H), 5.36 (s, 2H), 7.16 (dd, J = 5.1, 0. 7 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 0.7 Hz, 1H).

Example 18
3-((6-Bromo-3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetan-3-yl) -1H-imidazo [4,5-c Synthesis of pyridin-2 (3H) -one 18

Compound 18 was prepared similarly to compound 16 using intermediates 16-5 and 11-d as starting materials. m / z = 472 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.96 (d, J = 6.5 Hz, 6H), 1.50-1.61 (m, 2H), 1.67 (m, J = 6. 5Hz, 1H), 4.26-4.49 (m, 2H), 5.02-5.24 (m, 4H), 5.38 (s, 2H), 5.65 (tdd, J = 7. 6, 7.6, 5.9, 5.8 Hz, 1H), 7.61 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.31. -8.50 (m, 2H), 8.66 (s, 1H)

Example 19
1-((6-Bromo-3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -3-cyclopropyl-1H-benzo [d] imidazol-2 (3H) -one 30 synthesis

Compound 30 was prepared analogously to compound 16 using intermediates 16-5 and 13-d as starting materials. m / z = 455 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.94 (d, J = 6.5 Hz, 6H), 1.00-1.07 (m, 2H), 1.14 (m, J = 7. 3, 1.5 Hz, 2H), 1.41-1.54 (m, 2H), 1.66 (m, J = 13.4, 6.6, 6.6, 6.6 Hz, 1H), 2 .90 (tdd, J = 6.9, 6.9, 3.8, 3.5 Hz, 1H), 4.32-4.46 (m, 2H), 5.34 (s, 2H), 7. 03 (m, J = 7.7, 1.4 Hz, 1H), 7.09 (td, J = 7.7, 1.3 Hz, 1H), 7.20 (dd, J = 7.7, 0. 0). 6 Hz, 1 H), 7.28 (dd, J = 7.7, 0.6 Hz, 1 H), 8.15 (d, J = 2.0 Hz, 1 H), 8.40 (d, J = 2.0 Hz) , 1H)

Example 20
1-cyclopropyl-3-((3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridin-2 (3H) -one Synthesis of 24

Intermediate 16 (0.49 g, 1.09 mmol) in methanol (30 mL) to potassium acetate (0.128 g, 1.3 mmol), thiophenol (0.5 mL) and wet 10% Pd / C (0.2 g) Was added. The mixture was stirred at 25 ° C. under a hydrogen atmosphere. After consumption of H ₂ (1 eq), the catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in water and dichloromethane. The resulting mixture was continuously extracted with dichloromethane, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography using dichloromethane / methanol. The title compound 24 was collected as a white powder (333 mg, 81%). m / z = 377 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.97 (d, J = 6.8 Hz, 6H), 1.03-1.06 (m, 2H), 1.15-1.21 (m, 2H), 1.51-1.60 (m, 2H), 1.67-1.71 (m, 1H), 2.9-2.95 (m, 1H), 4.37, 4.44 ( m, 2H), 5.38 (s, 1H), 7.14 (dd, J = 5.3, 0.8 Hz, 1H), 7.22 (dd, J = 8.0, 4.8 Hz, 1H) ), 8.02 (dd, J = 8.2, 1.4 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.38 (dd, J = 4.8, 1.H). 5Hz, 1H), 8.58 (s, 1H)

Example 21
2-((1-Cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -3-isopentyl-3H-imidazo [4,5-b] pyridine Synthesis of -6-carboxylate 26

  Compound 16 (1 g, 2.15 mmol), palladium acetate (9.8 mg, 0.043 mmol), 1,3-bis (diphenylphosphino) propane (35.4 mg, 0.086 mmol), acetic acid in THF (100 mL) A mixture of potassium (316 mg, 3.22 mmol) and methanol (10 mL) was charged into an autoclave under a nitrogen atmosphere.

The autoclave was sealed and pressurized to 20 bar carbon monoxide and reacted at 125 ° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered over an acrodisc. The solvent was evaporated and the residue was purified by column chromatography using ethyl acetate / methanol. The title compound 26 was collected as a white powder (870 mg, 91%). m / z = 435 (M + H) ⁺ .
¹ H NMR (360 MHz, chloroform-d) δ ppm 0.98 (d, J = 6.6 Hz, 6H), 1.18 (m, J = 5.9 Hz, 2H), 1.52-1.61 ( m, 2H), 1.61-1.78 (m, 1H), 2.93 (tdd, J = 6.9, 6.9, 3.7, 3.5 Hz, 1H), 3.97 (s) 3H), 4.35-4.50 (m, 2H), 5.39 (s, 2H), 7.16 (d, J = 5.1 Hz, 1H), 8.35 (d, J = 5). .1 Hz, 1 H), 8.58 (s, 1 H), 8.64 (d, J = 1.8 Hz, 1 H), 9.06 (d, J = 1.8 Hz, 1 H)

Example 22
2-((1-Cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -3-isopentyl-3H-imidazo [4,5-b] pyridine Synthesis of -6-carboxylic acid 28

Compound 26 (0.84 g, 1.89 mmol) was dissolved in THF (15 mL), and lithium hydroxide (544 mg, 22.7 mmol) dissolved in water (10 mL) was added. The resulting mixture was stirred at room temperature overnight. The pH of the resulting mixture was adjusted to pH 4 by adding a 1M solution of hydrochloric acid. The mixture was then extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated. The title compound 28 was isolated as a white powder (690 mg, 84%). m / z = 421 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.94 (d, J = 5.8 Hz, 8H), 1.081-1.12 (m, 2H), 1.60-1.65 (m , 3H), 3.00 (br.s., 1H), 4.40-4.45 (m, 2H), 5.48 (s, 2H), 7.30 (d, J = 5.3 Hz, 2H), 8.27 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 8.43 (d, J = 1.3 Hz, 1H), 8.91 (d, J = 1.3Hz, 1H)

Example 23
2-((1-Cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -3-isopentyl-3H-imidazo [4,5-b] pyridine Synthesis of -6-carbonitrile 27

Compound 16 (0.5, 1 mmol), dichloro (diphenylphosphinoferrocene) palladium (78.7 mg, 0.108 mmol), dicyanozinc (0.505 g, 4.3 mmol) and dioxane (10 mL) under nitrogen atmosphere A mixture of triethylamine (0.6 mL, 4.3 mmol) was irradiated in a microwave reactor at 125 ° C. for 1 hour. The resulting reaction mixture was cooled to room temperature and then filtered over dicalite. The filtrate was evaporated to dryness. The product was purified by column chromatography using EtOAc / MeOH 8-2. The title compound 27 was isolated as a white solid (200 mg, 45%). m / z = 402 (M + H) ⁺ .
¹ H NMR (360 MHz, chloroform-d) δ ppm 0.95-1.08 (m, 2H), 1.03 (d, J = 6.2 Hz, 6H), 1.17-1.29 (m, 3H), 1.64-1.80 (m, 2H), 2.91-3.05 (m, 1H), 4.38-4.49 (m, 2H), 5.44 (s, 2H) , 7.27-7.31 (m, 1H), 8.17-8.33 (m, 1H), 8.49-8.58 (m, 1H), 8.62 (d, J = 1. 8Hz, 1H), 8.89-8.99 (m, 1H)

Example 24
3-((6- (Aminomethyl) -3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c] pyridine -2 (3H) -one 17 synthesis

Compound 27 (125 mg, 0.31 mmol) in methanol / NH ₃ (100 mL) was hydrogenated overnight at 20 ° C. using Raney nickel (50 mg) as a catalyst. After consumption of H ₂ ( ₂ eq), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography using dichloromethane / MeOH / NH ₃ . The title compound 17 was isolated as a white solid (25.5 mg, 20%). m / z = 406 (M + H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.92 (d, J = 6.3 Hz, 8H), 1.03-1.13 (m, 2H), 1.45 to 1.69 (m , 3H), 2.99 (tdd, J = 7.0, 7.0, 3.6, 3.5, Hz, 1H), 3.81 (s, 2H), 4.26-4.41 ( m, 2H), 5.42 (s, 2H), 7.29 (dd, J = 5.3, 0.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 8. 25 (d, J = 5.3 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.37 (s, 1H)

Example 25
2-((1-Cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -3-isopentyl-3H-imidazo [4,5-b] pyridine Synthesis of -6-ylboronic acid 23

Compound 16 (0.5 g, 1 mmol), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bis (1 in dioxane (20 mL) under argon atmosphere , 3,2-dioxaborolane (0.382 g, 1.5 mmol) and potassium acetate 0.16 g, 1.6 mmol) was stirred at room temperature for 10 minutes. Dichloro (diphenylphosphinoferrocene) palladium (39 mg, 0.05 mmol) was added to the resulting mixture. The resulting mixture was heated to 115 ° C. for 3 hours. The mixture was cooled to room temperature and then the solvent was removed. The residue (23-1) was dissolved in acetonitrile (40 mL), and 6M aqueous hydrochloric acid solution (1.7 mL, 10 mmol) was added. The resulting mixture was stirred for 2 hours at 110 ° C. The mixture was cooled to room temperature, water (30 mL) was added and the pH was adjusted to 7 by the addition of 7N ammonia solution in methanol. The resulting mixture was concentrated and the residue was purified by preparative HPLC. The title compound 23 was isolated as a white solid (309 mg, 67%). m / z = 421 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.92 (d, J = 6.5 Hz, 8H), 1.08-1.16 (m, 2H), 1.47-1.71 (m , 3H), 2.99 (tdd, J = 7.0, 7.0, 3.6, 3.5 Hz, 1H), 4.35 (m, J = 7.8 Hz, 2H), 5.43 ( s, 2H), 7.29 (d, J = 5.0 Hz, 1H), 8.21 (s, 2H), 8.25 (d, J = 5.3 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.38 (s, 1H), 8.68 (d, J = 1.5 Hz, 1H)

Example 26
3-((6-Bromo-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c Synthesis of pyridin-2 (3H) -one 19

Step 1: Synthesis of 5-bromo-N- (4- (tert-butyldiphenylsilyloxy) -3-nitropyridin-2-amine 19-1

In CH ₃ CN (200mL), 5- bromo-2-chloro-3-nitropyridine (CAS
67443-38-3) (33 g, 101 mmol), 4- (tert-butyldiphenylsilyloxy) butan-1-amine 8-b (20 g, 84.2 mmol), potassium carbonate (23.3 g, 168 mmol) and iodide A mixture of potassium (1.4 g, 8.4 mmol) was stirred at 20 ° C. for 15 hours. The resulting mixture was treated with CH ₂ Cl ₂ (400 mL) and water (400 mL). The separated aqueous layer was extracted with CH ₂ Cl ₂ (2 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. Intermediate 19-1 was obtained (44 g, 90%). m / z = 530 (M + H) ⁺ .

Step 2: 5-Bromo ^-N 2 - (4- (tert- butyldiphenylsilyloxy) butyl) pyridine-2,3-diamine 19-2

Intermediate 19-1 (48 g, 84 mmol) was dissolved in acetic acid (270 mL) and water (25 mL). The resulting mixture was warmed to 50 ° C. Iron (Fe) (36.1 g, 647 mmol) was added to the mixture very slowly over 20 minutes. The mixture was stirred for 2 hours at 50 ° C. and cooled to room temperature. Water (400 mL) was added and the mixture was filtered through a celite pad. The residue collected on celite was washed with water. The filtrate was treated with ethyl acetate (2 × 300 mL). The organic layer was separated and washed with water (2 × 400 mL) and brine (500 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was coevaporated with toluene under reduced pressure to give intermediate 19-2 (40 g, 90%).

Steps 3, 4 and 5: Synthesis of (6-Bromo-3- (4- (tert-butyldiphenylsilyloxy) butyl) -3H-imidazo [4,5-b] pyridin-2-yl) methanol 19-5

  Intermediate 19-5 was prepared similarly to Intermediate 10-5 in a three-step synthesis starting from Intermediate 19-2.

Step 6: 3-((6-Bromo-3- (4- (tert-butyldiphenylsilyloxy) butyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl Synthesis of -1H-imidazo [4,5-c] pyridin-2 (3H) -one 19-6

Intermediate 19-6 was prepared in the same manner as Compound 16 using Intermediates 19-5 and 10-d as starting materials. m / z = 696 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.94-1.05 (m, 11H), 1.13-1.21 (m, 2H), 1.51-1.58 (m, 2H) , 1.73-1.91 (m, 2H), 2.87 (tdd, J = 6.9, 6.9, 3.8, 3.5 Hz, 1H), 3.63 (t, J = 6) .1 Hz, 2H), 4.42 (t, J = 7.5 Hz, 2H), 5.31 (s, 2H), 7.09 (dd, J = 5.3, 0.5 Hz, 1H), 7 .30-7.36 (m, 4H), 7.38 (m, J = 7.3 Hz, 2H), 7.55-7.65 (m, 4H), 8.15 (d, J = 2. 0 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H)

Step 7: 3-((6-Bromo-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4 Synthesis of 5-c] pyridin-2 (3H) -one 19

Intermediate 19-6 (1.65 g, 2.32 mmol) was dissolved in methanol (40 mL) and then ammonium fluoride (0.206 g, 5.58 mmol) was added. The resulting mixture was stirred at reflux for 56 hours. The instinct mixture was allowed to cool to room temperature and then the solvent was removed. The residue was purified by column chromatography using dichloromethane / methanol to give the product as a white solid (1 g, 92%). m / z = 458 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.87-0.96 (m, 2H), 1.07 (m, J = 2.0 Hz, 2H), 1.37-1.51 (m , 2H), 1.69-1.83 (m, 2H), 3.00 (tdd, J = 7.0, 7.0, 3.6, 3.5 Hz, 1H), 3.35-3. 44 (m, 2H), 4.37 (t, J = 7.5 Hz, 2H), 4.44 (t, J = 5.1 Hz, 1H), 5.45 (s, 2H), 7.29 ( dd, J = 5.3, 0.8 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.37 (d , J = 0.5 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H)

Example 27
3-((6-Bromo-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetan-3-yl) -1H-imidazo [ Synthesis of 4,5-c] pyridin-2 (3H) -one 20

Step 1: 3-((6-Bromo-3- (4-tert-butyldiphenylsilyloxy) butyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetane- Synthesis of 3-yl) -1H-imidazo [4,5-c] pyridin-2 (3H) -one 20-1

Intermediate 20-1 was prepared in the same manner as Intermediate 19-6 using Intermediates 19-5 and 11-d as starting materials. m / z = 712 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 1.01 (s, 9H), 1.56 (s, 2H), 1.86 (m, J = 7.6, 7.6, 7.6, 7.6 Hz, 2H), 3.64 (t, J = 6.1 Hz, 2H), 4.40 (t, J = 7.4 Hz, 2H), 5.03-5.13 (m, 4H), 5.33 (s, 2H), 5.51-5.63 (m, 1H), 7.31-7.37 (m, 4H), 7.39 (d, J = 7.0 Hz, 2H), 7.54-7.58 (m, 1H), 7.61 (dd, J = 8.0, 1.5 Hz, 4H), 8.15 (d, J = 2.0 Hz, 1H), 8.39 (D, J = 2.0 Hz, 1H), 8.41 (d, J = 5.3 Hz, 1H), 8.66 (s, 1H)

Step 2: 3-((6-Bromo-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1- (oxetan-3-yl) -1H Synthesis of imidazo [4,5-c] pyridin-2 (3H) -one 20

Intermediate 20 was prepared in the same manner as Compound 19 using Intermediate 20-1 as the starting material. m / z = 474 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 1.56-1.67 (m, 2H), 1.86 (qd, J = 7.6, 7.4 Hz, 2H), 2.22 (br. s, 1H), 3.69 (t, J = 6.0 Hz, 2H), 4.38-4.51 (m, 2H), 5.04-5.21 (m, 4H), 5.40 ( s, 2H), 5.62 (tt, J = 7.7, 5.8 Hz, 1H), 7.61 (dd, J = 5.4, 0.6 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1 H), 8.32-8.49 (m, 2 H), 8.73 (d, J = 0.5 Hz, 1 H)

Example 28
3-((6-Chloro-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4,5-c Synthesis of pyridin-2 (3H) -one 21

Step 1: 3-((3- (4-tert-butyldiphenylsilyloxy) butyl) -6-chloro-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl- Synthesis of 1H-imidazo [4,5-c] pyridin-2 (3H) -one 21-2

  Intermediate 21-1 was prepared similarly to Intermediate 19-5 by a 5-step synthesis using 2,5-dichloro-3-nitropyridine (CAS 21427-62-3) as the starting material.

Intermediate 21-2 was prepared in the same manner as Intermediate 19-6 using Intermediates 21-1 and 10-d as starting materials.
m / z = 652 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.97 to 1.04 (m, 11H), 1.13 to 1.21 (m, 2H), 1.46 to 1.64 (m, 2H) , 1.82-1.91 (m, 2H), 2.88 (tdd, J = 7.0, 7.0, 3.6, 3.5 Hz, 1H), 3.63 (t, J = 6) .1 Hz, 2H), 4.43 (t, J = 7.4 Hz, 2H), 5.31 (s, 2H), 7.09 (d, J = 5.3 Hz, 1H), 7.29-7 .36 (m, 4H), 7.38 (m, J = 7.3 Hz, 2H), 7.60 (dd, J = 7.9, 1.4 Hz, 4H), 8.00 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.59 (s, 1H)

Step 2: 3-((6-Chloro-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4
Synthesis of 5-c] pyridin-2 (3H) -one 21

Compound 21 was prepared similarly to Intermediate 19 using Intermediate 21-2 as the starting material.
m / z = 414 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.98-1.06 (m, 2H), 1.17-1.21 (m, 2H), 1.64-1.68 (m, 2H) 1.84-1.91 (m, 2H), 2.36-2.41 (m, 1H), 2.95-3.01 (tdd, J = 7.0, 7.0, 3.6). , 3.5 Hz, 1H), 3.71 (q, J = 5.9 Hz, 2H), 4.41-4.50 (m, 2H), 5.37 (s, 2H), 7.15 (dd , J = 5.3, 0.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.66 (d, J = 0.8 Hz, 1H)

Example 29
1-cyclopropyl-3-((6-fluoro-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c Synthesis of pyridin-2 (3H) -one 22

Step 1: Synthesis of 5-fluoro-3-nitropyridin-2-yl 4-methylbenzenesulfonate 22-1

To a mixture of 5-fluoro-3-nitropyridin-2-ol (24.2 g, 153 mmol, CAS 136888-20-3), tosyl chloride (33.4 g, 176 mmol) in dichloromethane (1000 mL) was added triethylamine (44 mL, 304 mmol). ) Was added at room temperature under a nitrogen atmosphere. At the end of the addition, DMAP (3.7 g, 30 mmol) was added. The resulting mixture was stirred for 16 hours at 25 ° C. Dichloromethane (500 mL) was added and the mixture was washed successively with 1N aqueous hydrochloric acid (2 × 500 mL) and brine (500 mL). The separated aqueous layer was extracted with CH ₂ Cl ₂ (400 mL). The combined organic layers were dried over Na ₂ SO _{4 and} filtered through a silica pad (50 g). The filtrate was purified by flash chromatography (eluent: CH ₂ Cl ₂ ) to give intermediate 22-1 (34 g, 67%).

Step 2: Synthesis of N- (4- (tert-butyldiphenylsilyloxy) butyl-5-fluoro-3-nitropyridin-2-amine 22-2

  Intermediate 22-2 was prepared in the same manner as Intermediate 19-1 using Intermediates 22-1 and 8-b as starting materials.

Steps 3, 4, 5, 6 and 7: 3-((3- (4-tert-butyldiphenylsilyloxy) butyl) -6-fluoro-3H-imidazo [4,5-b] pyridin-2-yl) Synthesis of methyl) -1-cyclopropyl-1H-imidazo [4,5-c] pyridin-2 (3H) -one 22-7

Intermediate 22-7 was prepared similarly to Intermediate 19-5 in 5 steps using Intermediate 22-2 as the starting material. m / z = 635 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.95-1.12 (m, 2H), 1.00 (s, 9H), 1.09-1.17 (m, 2H), 1.52 -1.64 (m, 2H), 1.76-1.89 (m, 2H), 2.88 (tdd, J = 7.0, 7.0, 3.6, 3.5Hz, 1H), 3.64 (t, J = 6.3 Hz, 2H), 4.43 (t, J = 7.4 Hz, 2H), 5.31 (s, 2H), 7.09 (dd, J = 5.3) , 0.8 Hz, 1H), 7.30-7.42 (m, 6H), 7.58-7.64 (m, 4H), 7.72 (dd, J = 8.7, 2.6 Hz, 1H), 8.24 (dd, J = 2.5, 1.8 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.60 (s, 1H)

Step 8: 1-cyclopropyl-3-((6-fluoro-3- (4-hydroxybutyl) -3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4 Synthesis of 5-c] pyridin-2 (3H) -one 22

Intermediate 22 was prepared in the same manner as Compound 19 using Intermediate 22-7 as the starting material. m / z = 397 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.99-1.07 (m, 2H), 1.14-1.21 (m, 2H), 1.65 (quin, J = 6.6 Hz, 2H), 1.85 (qd, J = 7.5, 7.3 Hz, 2H), 2.48 (t, J = 5.3 Hz, 1H), 2.95 (tdd, J = 7.0, 7 0.0, 3.6, 3.5 Hz, 1H), 3.71 (m, J = 4.0 Hz, 2H), 4.41-4.51 (m, 2H), 5.37 (s, 2H) 7.15 (dd, J = 5.3, 0.8 Hz, 1H), 7.74 (dd, J = 8.5, 2.5 Hz, 1H), 8.26 (dd, J = 2.5 , 1.8 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.66 (d, J = 0.5 Hz, 1H)

Example 30
4-chloro-3-((3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-isopropyl-1H-imidazo [4,5-c] pyridine-2 (3H ) -On 25 synthesis

Step 1: Synthesis of N-isopentyl-3-nitropyridin-2-amine 25-1

Intermediate 25-1 is prepared in the same manner as Intermediate 7-1 using commercially available 2-chloro-3-nitropyridine (CAS 5470-18-8) and isopentylamine (CAS 107-85-7). did.
m / z = 210 (M + H) ⁺ .

Step 2: Synthesis of N ² -isopentylpyridine-2,3-diamine 25-2

Intermediate 25-2 was prepared in the same manner as Intermediate 7-2 using Intermediate 25-1 as the starting material. m / z = 178 (M + H) ⁺ .

Step 3: Synthesis of 3-isopentyl-2- (trichloromethyl) -3H-imidazo [4,5-b] pyridine 25-3

Intermediate 25-2 (17.5 g, 97.6 mmol) was dissolved in acetic acid (220 mL). Methyl 2,2,2-trichloroacetimidate (CAS 2533-69-9) (12.13 mL, 97.6 mmol) was quickly added to the resulting mixture. The resulting mixture was stirred for 48 hours at 50 ° C. The mixture was cooled to room temperature and poured onto ice / water solution. The pH was adjusted to pH = 5 by adding sodium carbonate. The resulting mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed successively with saturated NaHCO ₃ solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using CH ₂ CI ₂ to CH ₂ Cl ₂ / EtOAc as eluent to give an oil that became a solid when dried under vacuum (23 g, 77%). m / z = 307 (M + H) ⁺ .

Step 4: Synthesis of methyl 3-isopentyl-3H-imidazo [4,5-b] pyridine-2-carboxylate 25-4

Intermediate 25-3 (20 g, 65.22 mmol) was dissolved in MeOH (400 mL) and sodium carbonate (6.9 g, 65.22 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour and sodium methanolate (25%, 6 mL, 26.1 mmol) was added. The resulting mixture was refluxed for 48 hours. The mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography using CH ₂ Cl ₂ to CH ₂ Cl ₂ / EtOAc 1/1 as eluent. Intermediate 25-4 was isolated as a white powder after evaporation (9.52 g, 59%). m / z = 248 (M + H) ⁺ .

Step 5: Synthesis of (3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methanol 25-5

Intermediate 25-4 (9.52 g, 38.5 mmol) was dissolved in dry THF (125 mL). The mixture was cooled to 0 ° C. in an ice bath. Lithium aluminum hydride (1.46 g, 38.5 mmol) was added in small portions. The resulting mixture was stirred at 0 ° C. for 10 minutes and then at room temperature overnight. A saturated NaHCO ₃ solution (10 mL) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. EtOAc (200 mL) was then added. The organic layer was washed with water (100 mL), then dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using EtOAc / MeOH / NH ₃ 9/1 as eluent. After evaporation, intermediate 25-5 was isolated as a white powder (0.58 g, 7%). m / z = 220 (M + H) ⁺ .

Step 6: 4-Chloro-3- (3-isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-isopropyl-1H-imidazo [4,5-c] pyridine-2 Synthesis of (3H) -one 25

Compound 25 was prepared in the same manner as compound 10 using intermediates 25-5 and 14-d as starting materials. m / z = 414 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 1.04 (d, J = 6.4 Hz, 6H), 1.59 (d, J = 7.0 Hz, 6H), 1.68-1.85 ( m, 3H), 4.37-4.44 (m, 2H), 4.76 (spt, J = 7.1 Hz, 1H), 5.66 (s, 2H), 7.10 (d, J = 5.5 Hz, 1H), 7.15 (dd, J = 8.0, 4.7 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 8.09 (d , J = 5.5 Hz, 1H), 8.34 (dd, J = 4.8, 1.5 Hz, 1H)

3- (3-Isopentyl-3H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] Synthesis of pyridine-4-carbonitrile 29

Compound 25 (0.075 g, 0.182 mmol), tetrakis (triphenyl-phosphine) palladium (41 mg, 0.036 mmol) and dicyanozinc (0.042 g, 0.363 mmol) in DMF (3 mL) under a nitrogen atmosphere. The mixture was irradiated in a microwave reactor at 170 ° C. for 30 minutes. The resulting mixture was allowed to cool to room temperature, then filtered through an acrodisc filter and evaporated to dryness. The residue was purified by column chromatography using EtOAc. The title compound 29 was isolated as a white solid (60 mg, 81%).
m / z = 404 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00 (d, J = 6.6 Hz, 6H), 1.52 (d, J = 7.0 Hz, 6H), 1.68 (spt, J = 6.6 Hz, 1H), 1.74-1.83 (m, 2H), 4.38-4.46 (m, 2H), 4.74 (spt, J = 7.2 Hz, 1H), 5 .71 (s, 2H), 7.23 (dd, J = 8.0, 4.7 Hz, 1H), 7.81 (d, J = 5.3 Hz, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 8.34 (dd, J = 4.9, 1.4 Hz, 1H), 8.37 (d, J = 5.3 Hz, 1H)

Example 31
1-cyclopropyl-3- (1-isopentyl-1H-imidazo [4,5-c] pyridin-2-yl) methyl-1H-imidazo [4,5-c] pyridin-2 (3H) -one Composition

Compound 33 was prepared in the same manner as Compound 7 using 4-chloro-3-nitropyridine (CAS 13091-23-1) and isopentylamine (CAS 107-85-7) as starting materials. m / z = 377 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.99 (d, J = 6.6 Hz, 6H), 1.00-1.05 (m, 2H), 1.13-1.23 (m, 2H), 1.44-1.55 (m, 2H), 1.65-1.78 (m, 1H), 2.86-2.98 (m, 1H), 4.28-4.36 ( m, 2H), 5.38 (s, 2H), 7.14 (dd, J = 5.4, 0.7 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 8. 34 (d, J = 5.3 Hz, 1H), 8.43 (d, J = 5.7 Hz, 1H), 8.64 (s, 1H), 9.08 (d, J = 1.0 Hz, 1H) )

Example 32
Synthesis of 1-cyclopropyl-3- (1-isopentyl-1H-imidazo [4,5-c] pyridin-2-yl) methyl-1H-benzo [d] imidazol-2 (3H) -one 31

Compound 31 was prepared in the same manner as compound 33 using intermediate 13-d as starting material in the last step. m / z = 376 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.96 (d, J = 6.5 Hz, 6H), 0.99-1.07 (m, 2H), 1.08-1.20 (m, 2H), 1.37-1.48 (m, 2H), 1.68 (dquin, J = 13.3, 6.7, 6.7, 6.7, 6.7 Hz, 1H), 2.90. (Tdd, J = 6.9, 6.9, 3.8, 3.5 Hz, 1H), 4.25-4.41 (m, 2H), 5.37 (s, 2H), 7.07- 7.15 (m, 2H), 7.16-7.23 (m, 1H), 7.25 (dd, J = 5.8, 1.0 Hz, 1H), 7.32-7.43 (m , 1H), 8.41 (d, J = 5.8 Hz, 1H), 9.09 (d, J = 0.8 Hz, 1H)

Example 33
1-cyclopropyl-5-fluoro-3- (1-isopentyl-1H-imidazo [4,5-c] pyridin-2-yl) methyl-1H-benzo [d] imidazol-2 (3H) -one Composition

Compound 32 was prepared similarly to compound 33 using intermediate 12-d as starting material in the last step. m / z = 394 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.97 (d, J = 6.5 Hz, 6H), 1.00-1.05 (m, 2H), 1.10-1.17 (m, 2H), 1.40-1.50 (m, 2H), 1.70-1.73 (m, 1H), 2.88-3.02 (m, 1H), 4.29-4.39 ( m, 2H), 5.33 (s, 2H), 6.74-6.84 (m, 1H), 7.09 (dd, J = 8.5, 4.5 Hz, 1H), 7.19 ( dd, J = 8.5, 2.3 Hz, 1H), 7.24-7.27 (m, 1H), 8.42 (d, J = 5.5 Hz, 1H), 9.10 (s, 1H) )

Example 34
3-((1-Isopentyl-1H-imidazo [4,5-c] pyridin-2-yl) methyl-1- (oxetan-3-yl) -1H-imidazo [4,5-c] pyridine-2 ( Synthesis of 3H) -one 36

Compound 36 was prepared similarly to compound 33 using intermediate 11-d as starting material in the last step. m / z = 393 (M + H) ⁺ .

3-((1- (4-Benzyloxy) butyl) -4-chloro-1H-imidazo [4,5-c] pyridin-2-yl) methyl-1-cyclopropyl-1H-imidazo [4,5- c] Synthesis of Pyridin-2 (3H) -one 38

Step 1: Synthesis of 1- (4-benzyloxy) butyl) -4-chloro-2- (diethoxymethyl) -1H-imidazo [4,5-c] pyridine 38-2 Intermediate 38-1 was Similar to intermediate 10-3 in two steps using 2,4-dichloro-3-nitropyridine (CAS 5975-12-2) and 4-aminobut-1-ol (CAS 13325-10-5) as raw materials Manufactured.

To a solution of intermediate 38-1 (8.05 g, 24.55 mmol) stirred in dry THF (100 mL) and cooled to 0 ° C., benzyl bromide (3.06 mL, 25.8 mmol), tetrabutylammonium iodide. (90.7 mg, 0.24 mmol) was added. To the resulting mixture was added sodium hydride (1.08 g, 27.02 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in dichloromethane (200 mL). The resulting mixture was poured into ice / water and stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography using EtOAc. The title intermediate 38-2 was isolated as a yellow oil (8.75 g, 85%). m / z = 419 (M + H) ⁺ .

Compound 38 was prepared similarly to compound 10 in 3 steps using intermediate 38-2 as starting material. m / z = 504 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.94-1.02 (m, 2H), 1.13-1.21 (m, 2H), 1.59-1.76 (m, 4H) , 2.88 (tdd, J = 7.0, 7.0, 3.6, 3.5 Hz, 1H), 3.45 (t, J = 5.5 Hz, 2H), 4.35 (t, J = 7.4 Hz, 2H), 4.44 (s, 2H), 5.40 (s, 2H), 7.01-7.09 (m, 1H), 7.18 (d, J = 5.8 Hz) , 1H), 7.22-7.37 (m, 5H), 8.15 (d, J = 5.8 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.68. (D, J = 0.5Hz, 1H)

Example 35
1-cyclopropyl-3-((1- (4-hydroxybutyl) -1H-imidazo [4,5-c] pyridin-2-yl) methyl-1H-imidazo [4,5-c] pyridine-2 ( Synthesis of 3H) -one 35

To intermediate 38 (0.5 g, 0.99 mmol) in methanol (100 mL) was added potassium acetate (0.146, 1.5 mmol) and wet 10% Pd / C (0.2 g). The reaction mixture was stirred at 25 ° C. under a hydrogen atmosphere. After consumption of H ₂ (1 eq), the catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in water and dichloromethane. The resulting mixture was extracted sequentially with dichloromethane, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography using dichloromethane / methanol. The title compound 35 was collected as a white powder (125 mg, 31%). m / z = 379 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.86-0.99 (m, 2H), 1.08 (m, J = 5.3 Hz, 2H), 1.37-1.54 (m , 2H), 1.71 (ddd, J = 14.6, 7.7, 7.4 Hz, 2H), 3.01 (tt, J = 6.9, 3.2 Hz, 1H), 3.37−. 3.48 (m, 2H), 4.38 (t, J = 7.4 Hz, 2H), 4.48 (t, J = 5.0 Hz, 1H), 5.45 (s, 2H), 7. 29 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1 H), 8.39 (s, 1 H), 8.87 (s, 1 H)

Example 36
1-cyclopropyl-3-((4- (dimethylamino) -1- (4-hydroxybutyl) -1H-imidazo [4,5-c] pyridin-2-yl) methyl-1H-imidazo [4,5 -C] Synthesis of Pyridin-2 (3H) -one 37

Compound 38 (0.5 g, 0.99 mmol) was placed in a microwave tube and dimethylamine (2M solution in MeOH, 10 mL) was added. The resulting mixture was heated to 125 ° C. in a microwave oven for 4 hours. The reaction mixture was cooled to room temperature and then evaporated to dryness. The residue (510 mg) containing intermediate 37-1 was dissolved in methanol (50 mL) and potassium acetate (0.195 g, 1.99 mmol) and wet 10% Pd / C (0.2 g) were added. The reaction mixture was stirred at 50 ° C. under a hydrogen atmosphere for 48 hours. After consumption of H ₂ (1 eq), the catalyst was filtered off and evaporated. The residue was dissolved in a mixture of water and dichloromethane. The resulting mixture was extracted sequentially with dichloromethane, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography using dichloromethane / methanol. The title compound 37 was collected as a white powder (140 mg, 32%). m / z = 422 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.86-0.93 (m, 2H), 1.07-1.12 (m, 2H), 1.33-1.44 (m, 2H) ), 1.48-1.62 (m, 2H), 2.97 (tdd, J = 7.0, 7.0, 3.6, 3.5 Hz, 1H), 3.33 (s, 6H) 3.3-3.38 (m, 2H), 4.22 (t, J = 7.5 Hz, 2H), 4.43 (t, J = 4.9 Hz, 1H), 5.34 (s, 2H),
6.80 (d, J = 5.5 Hz, 1H), 7.26 (d, J = 5.3 Hz, 1H), 7.78 (d, J = 5.8 Hz, 1H), 8.23 (d , J = 5.3 Hz, 1H), 8.44 (s, 1H)

Example 37
Synthesis of 1-cyclopropyl-3-((3-isopentyl-3H-imidazo [4,5-c] pyridin-1H-imidazo [4,5-c] pyridin-2 (3H) -one 34

Step 1: Synthesis of 3- (isopentylamino) -4-nitropyridine 1-oxide 34-1

3-Bromo-4-nitropyridine 1-oxide (CAS 1678-49-5, 10 g, 46 mmol) was dissolved in ethanol (400 mL). To the resulting mixture 3-methylbutan-1-amine (21.8 g, 250 mmol) was slowly added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (500 mL) and washed with saturated aqueous NaHCO ₃ (500 mL). The combined aqueous layer was extracted with CH ₂ Cl ₂ (3 × 150 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give intermediate 34-1 (9.8 g, 94%).

Synthesis of isopentyl pyridine-3,4-diamine 34-2 - ^{N 3:} Step 2

Intermediate 34-1 (15 g, 66 mmol) in methanol (600 mL) was hydrogenated (1 atm) overnight at 20 ° C. using Raney Ni (6 g) as a catalyst. After consumption of H ₂ (4 eq.), The catalyst was removed by filtration. The filtrate was concentrated to a pink residue and the residue was washed with tert-butyl methyl ether and CH ₃ CN to give intermediate 34-2 (7 g, 59%).
Compound 34 was prepared similarly to compound 10 in a 4-step synthesis using intermediate 34-2 as a starting material. m / z = 377 (M + H) ⁺ .
¹ H NMR (360 MHz, chloroform-d) δ ppm 0.9-1.1 (m, 2H), 1.00 (d, J = 6.6 Hz, 6H), 1.13-1.23 (m, 2H), 1.49-1.63 (m, 2H), 1.66-1.82 (m, 1H), 2.85-3.00 (m, 1H), 4.33-4.50 ( m, 2H), 5.38 (s, 2H), 7.15 (d, J = 5.5 Hz, 1H), 7.67 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.64 (s, 1H), 8.78 (s, 1H)

Example 38
3-((5-Chloro-1- (4,4,4-trifluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl-1-cyclopropyl-1H-imidazo [4 , 5-c] pyridin-2 (3H) -one 39

Step 1: Synthesis of (5-Chloro-1- (4,4,4-trifluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methanol 39-3 Prepared analogously to Intermediate 1-3 using 1-1 and 4,4,4-trifluorobutanal.

Step 2:
Compound 39 was prepared similarly to compound 1 using intermediates 39-3 and 10-d as starting materials. m / z = 451 (M + H) +.
¹ H NMR (400 MHz, chloroform-d) δ ppm 1.00 (s, 2H), 1.12-1.23 (m, 2H), 1.83-1.99 (m, 2H), 2.12 -2.31 (m, 2H), 2.91 (spt, J = 3.50 Hz, 1H), 4.38-4.54 (m, 2H), 5.38 (s, 2H), 7.13 (Dd, J = 5.27, 0.50 Hz, 1H), 7.27 (d, J = 8.28 Hz, 1H), 7.61 (d, J = 8.53 Hz, 1H), 8.36 ( d, J = 5.27 Hz, 1H), 8.77 (s, 1H)

Example 39
3-((5-Chloro-1- (4-fluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl-1-cyclopropyl-1H-imidazo [4,5-c] Synthesis of Pyridin-2 (3H) -one 40

  Compound 40 was made by two-step fluorination of compound 14.

Compound 14 (5.4 g, 13.1 mmol) and DABCO (4.4 g, 39.2 mmol) were added to dry CH ₂ Cl ₂ (50 mL) and the resulting solution was stirred at 0 ° C. under N ₂ . Tos-Cl (5.0 g, 26.2 mmol) was added in portions to this mixture at 0 ° C. The mixture was stirred at 15 ° C. for 2 hours. The mixture was washed with 1N HCl (2 × 20 mL), saturated NaHCO ₃ (40 mL) and brine (20 mL), dried over Na ₂ SO ₄ and evaporated to dryness. 7.3 g of product was obtained as a white powder (purity 85%, yield 98%). This tosylated intermediate (7.3 g, 12.9 mmol) was added to CH ₃ CN (HPLC grade, 70 mL). To this mixture was added TBAF (6.7 g, 25.7 mmol, dried by co-evaporation with toluene). The mixture was refluxed for 15 minutes. The solvent was removed under reduced pressure. Water (200 mL) was added to the mixture and the mixture was extracted with CH ₂ Cl ₂ (2 × 200 mL). The extracts were combined and concentrated under reduced pressure. The resulting residue is combined with 11 g of the previously obtained product (purity 80%) and then high performance liquid chromatography (CI8, eluent: CH ₃ CN / containing 0.5% TFA as buffer. and purified by the 15/85 of H ₂ 0 to 35/65). The collected fractions were combined and neutralized with NaHCO ₃ . The organic solvent was removed under reduced pressure. The mixture was filtered and the solid was washed with H ₂ O (200 mL). After drying under high vacuum, 3.075 g of product was obtained as a white powder (purity 98%). m / z = 415 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88-0.96 (m, 2H) 1.07 (m, J = 0.02 Hz, 2H) 1.60-1.85 (m, 4H ) 2.99 (tt, J = 6.96, 3.58 Hz, 1H) 4.45 (m, J = 5.65, 5.65 Hz, 4H) 5.46 (s, 2H) 7.30 (d , J = 5.27 Hz, 1H) 7.36 (d, J = 8.28 Hz, 1H) 8.19 (d, J = 8.53 Hz, 1H) 8.27 (d, J = 5.27 Hz, 1H) ) 8.41 (s, 1H).

Example 40
1-cyclopropyl-3-((1- (4,4,4-trifluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5- c] Synthesis of Pyridin-2 (3H) -one 41

  Compound 41 was prepared by Pd-catalyzed reduction of compound 39.

Compound 39 (1000 mg, 2.22 mmol) was dissolved in 30 mL MeOH and Pd / C (10%) and KOAc (218 mg, 2.22 mol) were added. The mixture was placed under H ₂ and hydrogenated overnight. The mixture was filtered over a plug of celite and evaporated. Compound 41 was purified by column chromatography on silica gel using a _CH 2 C1 ₂ as eluent to _{CH 2 Cl 2 / MeOH (NH} 3) 9-1. After evaporation, 550 mg (59% yield) of compound 41 was obtained as a white solid with a purity of 99%. m / z = 417 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.93-1.05 (m, 2H), 1.18 (s, 2H), 1.91 (s, 2H), 2.12-2.31 (M, 2H), 2.91 (tt, J = 6.93, 3.48 Hz, 1H), 4.46 (t, J = 7.80 Hz, 2H), 5.42 (s, 2H), 7 .14 (d, J = 5.27 Hz, 1H), 7.25 (dd, J = 8.28, 4.77 Hz, 1H), 7.66 (dd, J = 8.16, 1.38 Hz, 1H) ), 8.36 (d, J = 5.27 Hz, 1H), 8.59 (dd, J = 4.77, 1.51 Hz, 1H), 8.80 (s, 1H).

Example 41
1-cyclopropyl-3-((1- (4-fluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridine-2 Synthesis of (3H) -one 42

  Compound 42 was prepared analogously to compound 11 using intermediates 42-5 and 10-d as starting materials.

(1- (4-Fluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methanol 42-5 (958 mg, 4.3 mmol), 1-cyclopropyl-1H— in 30 mL dry THF To a suspension of imidazo [4,5-c] pyridin-2 (3H) -one 10-d (950 mg, 5.15 mmol) and triphenylphosphine (1350 mg, 5.15 mmol), (E) -diisopropyl diazene- 1,2-dicarboxylate (1.26 mL, 6.43 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed several times with diethyl ether to give the title product as a white powder (1036 mg, 63%). m / z = 381 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88-0.96 (m, 2H) 1.04-1.12 (m, 2H) 1.60-1.86 (m, 4H) 3 .00 (tt, J = 6.78, 3.26 Hz, 1H) 4.34-4.56 (m, 4H) 5.45 (s, 2H) 7.27 (dd, J = 8.16, 4 .64 Hz, 1H) 7.30 (d, J = 5.27 Hz, 1H) 8.08 (d, J = 7.28 Hz, 1H) 8.26 (d, J = 5.27 Hz, 1H) 8.37 (D, J = 4.02 Hz, 1H) 8.42 (s, 1H)

  Intermediate 42-5 was prepared in the same manner as Intermediate 11-5 using 4-fluorobutan-1-amine TFA salt and 3-fluoro-2-nitropyridine as starting materials.

Example 42
1-cyclopropyl-3-((1- (4,4-difluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] pyridine -2 (3H) -one 43 synthesis

  This compound was prepared similarly to compound 11 using intermediates 43-5 and 10-d as starting materials.

(1- (4,4-Difluorobutyl) -1H-imidazo [4,5-b] pyridin-2-yl) methanol 43-5 (470 mg, 1.9 mmol), 1-cyclopropyl in 14 mL dry THF To a suspension of -1H-imidazo [4,5-c] pyridin-2 (3H) -one 10-d (431 mg, 2.3 mmol) and triphenylphosphine (613 mg, 2.3 mmol), (E)- Diisopropyl diazene-1,2-dicarboxylate (0.6 mL, 2.9 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed several times with diethyl ether to give the title product as a white powder (450 mg, 58%). m / z = 399 (M + H) ⁺ .
¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88-0.96 (m, 2H) 1.04-1.12 (m, 2H) 1.79-1.99 (m, 4H) 2 .99 (tt, J = 7.00, 3.54 Hz, 1H) 4.43 (t, J = 7.28 Hz, 2H) 5.46 (s, 2H) 6.11 (tt, J = 57.00 , 4.30 Hz, 1H) 7.24-7.34 (m, 2H) 8.09 (dd, J = 8.28, 1.51 Hz, 1H) 8.27 (d, J = 5.27 Hz, 1H) ) 8.38 (dd, J = 4.77, 1.51 Hz, 1H) 8.43 (s, 1H)

  Intermediate 43-5 was prepared in a similar manner to Intermediate 11-5 using 4,4-difluorobutane-1-amine hydrochloride and 3-fluoro-2-nitropyridine as starting materials.

  4,4-Difluorobutane-1-amine hydrochloride 15-e can be prepared as described in Scheme 15 below.

Step 1: Synthesis of 2- (4,4-diethoxybutylcarbamoyl) benzoic acid 15-a Isobenzofuran-1,3-dione (10.5 g, 70.889 mmole), DMAP (824 mg, in THF (100 mL)) To a solution of 0.1 eq) and triethylamine (10.323 mL, 1.1 eq), 4,4-diethoxybutan-1-amine (12.095 g, 1 eq) was added dropwise at 0 ° C. over 10 minutes. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated under vacuum to produce compound 15-a (20.9 g, quantitative yield). This product was used in the next step without purification. m / z = 308 (M−H) ⁻

Step 2: Synthesis of 2- (4,4-diethoxybutyl) isoindoline-1,3-dione 15-b 2- (4,4-diethoxybutylcarbamoyl) benzoic acid in acetic anhydride (95 mL) 15 A mixture of -a (20.8 g, 67.235 mmole) and sodium acetate (2.757 g, 0.5 eq) was heated at 110 ° C for 3 hours. The reaction mixture was then cooled to room temperature and poured into 700 mL ice-water. After 2 hours of stirring, it was then extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO 3 solution, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the desired product 15-b (19.6 g, quantitative yield). . This product was used as such for the next reaction.

Step 3: Synthesis of 4- (1,3-dioxoisoindoline-2-yl) butanal 15-c 2- (4,4-diethoxybutyl) isoindoline-1,3-dione in THF (130 mL) To a 15-b (19.6 g, 67.274 mmole) solution was added PTSA monohydrate (734 mg, 0.05 eq) and water (17 mL, 14 eq). The reaction mixture was stirred for 72 hours at room temperature. Then water (3 mL) and PTSA monohydrate (150 mg) were added and stirring was continued overnight. The reaction mixture was then diluted with 300 mL EtOAc, washed with NaHCO ₃ then brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography using EtOAc as eluent to give 14 g of desired compound 15-c as a brown oil that solidified on standing (95% yield).
¹ H NMR (400 MHz, chloroform-d) δ ppm 2.03 (quin, J = 7.1 Hz, 2H), 2.54 (td, J = 7.3 Hz, 2H), 3.75 (t, J =
6.8 Hz, 2H), 7.70-7.74 (m, 2H), 7.79-7.92 (m, 2H), 9.78 (t, J = 1.lHz, 1H).

Step 4: Synthesis of 2- (4,4-difluorobutyl) isoindoline-1.3-dione 15-d Diethylaminodifluorosulfonium tetrafluoroborate (3.162 g, 13.81 mmole) in CH ₂ Cl ₂ (90 mL) at room temperature. ) Was added 4- (1,3-dioxoisoindoline-2-yl) butanal 15-c (2 g, 9.207 mmole) and triethylamine trihydrochloride (2.226 g, 1.5 eq). It was. The mixture was stirred overnight under N ₂ atmosphere. 100 mL of saturated NaHCO ₃ solution was added and stirred for 10 minutes until gas evolution ceased. The reaction mixture was then extracted with 150 mL DCM (2 ×). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude product was purified by flash chromatography using DCM as eluent to give 16 g (72% yield) of the desired compound 15-d as a yellowish oil. m / z = 240 (M + H) ^+
1 H NMR (400 MHz, chloroform-d) δ ppm 1.78-1.99 (m, 4H), 3.75 (t, J = 6.8 Hz, 2H), 5.86 (tt, J = 56. 5, 3. Hz), 7.68-7.77 (m, 2H), 7.81-7.90 (m, 2H).

Step 5: Synthesis of 4,4-difluorobutan-1-amine 15-e 2- (4,4-difluorobutyl) isoindoline-1,3-dione 15-d (8 g, 33.442 mmole) in 20 mL EtOH. ) And hydrazine (1.788 mL, 1.1 eq, 1.0 M in water) were heated at reflux for 2 hours. The mixture was then cooled with an ice bath. The resulting 2,3-dihydrophthalazine-1,4-dione precipitate was filtered off and the filtrate was concentrated in vacuo to give the desired compound 15-e (3.6 g). This compound was directly used in the next reaction.

Example 43
1-cyclopropyl-3-((1-isopentyl-5- (trifluoromethyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1H-imidazo [4,5-c] Synthesis of Pyridin-2 (3H) -one 44

  This compound was prepared similarly to compound 11 using intermediates 44-3 and 10-d as starting materials.

(1-Isopentyl-5- (trifluoromethyl) -1H-imidazo [4,5-b] pyridin-2-yl) methanol 44-3 (1.0 g, 3.5 mmol (purity 73%) in 24 mL dry THF )), 1-cyclopropyl-1H-imidazo [4,5-c] pyridin-2 (3H) -one 10-d (731.8 mg, 4.2 mmol) and triphenylphosphine (1.1 grams g, 4 (E) -diisopropyl diazene-1,2-dicarboxylate (1.0 mL, 5.2 mmol) was added to a suspension of. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and purified by preparative column chromatography to give 44 as a white solid (578.0 mg, 37%). m / z = 445 (M + H) ⁺ .
¹ H NMR (400 MHz, chloroform-d) δ ppm 1.02 (m, J = 6.50 Hz, 8H) 1.13-1.24 (m, 2H) 1.48-1.64 (m, 2H) 1.73 (dquin, J = 13.19, 6.49, 6.49, 6.49, 6.49 Hz, 1H) 2.92 (tt, J = 6.81, 3.48 Hz, 1H) 35-4.52 (m, 2H) 5.41 (s, 2H) 7.13 (d, J = 5.27 Hz, 1H) 7.61 (d, J = 8.28 Hz, 1H) 7.79 ( d, J = 8.28 Hz, 1H) 8.34 (d, J = 5.27 Hz, 1H) 8.68 (s, 1H).

  Intermediate 44-3 was prepared in the same manner as Intermediate 39-3 using Intermediate 44-1 and 3-methylbutanal as starting materials.

Example 45

Example 47
3-{[5-Chloro-1- (4-hydroxypentyl) -1H-imidazo [4,5-b] pyridin-2-yl] methyl} -1-cyclopropyl-1,3-dihydro-2H-imidazo Synthesis of [4,5-c] pyridin-2-one (67)
Step 1: 4- (5-Chloro-2-((1-cyclopropyl-2-oxo-1H-imidazo [4,5-c] pyridin-3 (2H) -yl) methyl) -1H-imidazo [4 , 5-b] pyridin-1-yl) butanal (67-1)

To alcohol 14 (5 g, 12.11 mmole) dissolved in DCM (80 mL) was added des-martin periodinane (6.934 g, 1.35 eq, CAS 87413-09-0). The resulting mixture was stirred at room temperature overnight. Diethyl ether was added (150 mL) and the mixture was stirred for 15 minutes. The mixture was filtered and the filtrate was quickly washed with aqueous Na ₂ S ₂ O ₃ solution, dried over Na ₂ SO ₄ , filtered and evaporated. The resulting solid was washed again with a 5% methanol solution in dichloromethane and the filtrate was washed with aqueous Na ₂ S ₂ O ₃ and dried over Na ₂ SO ₄ . The solution was concentrated to give aldehyde 67-1 as a pale yellow solid (4.6 g, 93% yield). This solid was used as such in the next step. LCMS m / z = 411 (M + H) ⁺

Step 2: 3-{[5-Chloro-1- (4-hydroxypentyl) -1H-imidazo [4,5-b] pyridin-2-yl] methyl} -1-cyclopropyl-1,3-dihydro- Synthesis of 2H-imidazo [4,5-c] pyridin-2-one (67)

4- {5-Chloro-2-[(1-cyclopropyl-2-oxo-1,2-dihydro-3H-imidazo [4,5-c] in dry THF (50 mL) in a 100 mL dry flask. Pyridin-3-yl) methyl] -1H-imidazo [4,5-b] pyridin-1-yl} butanal 67-1 (1.5 g, 3.6 mmol) is dissolved and −20 ° C. under N ₂ atmosphere. Until cooled. Then excess methylmagnesium iodide (3M in THF) (1.8 mL, 5.5 mmol, 1.5 eq.) Was slowly added dropwise via a syringe to the cooled solution. The solution was warmed to ambient temperature and stirred for 4 hours. The solution was diluted with 30 mL NaHCO ₃ solution and extracted with EtOAC (30 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under vacuum. The crude product was purified by RP SunFire Prep column (C18 OBD-10 μm, 30 × 150 mm) using a 0.25% NH ₄ HCO ₃ solution in water-methanol solution to give 3-{[5-chloro-1- (4-Hydroxypentyl) -1H-imidazo [4,5-b] pyridin-2-yl] methyl} -1-cyclopropyl-1,3-dihydro-2H-imidazo [4,5-c] pyridine-2 -350 mg (22%) of ON (67) was obtained as a white solid.
¹ H NMR (400 MHz, chloroform-d) δ ppm 0.99-1.05 (m, 2H) 1.13-1.22 (m, 5H) 1.43-1.57 (m, 2H) 77-1.91 (m, 2H) 2.11 (br.s, 1H) 2.89-2.98 (m, 1H) 3.81-3.90 (m, 1H) 4.32-4. 50 (m, 2H) 5.40 (s, 2H) 7.13 (dd, J = 5.27, 0.75 Hz, 1H) 7.23 (d, J = 8.53 Hz, 1H) 7.65 ( d, J = 8.28 Hz, 1H) 8.34 (d, J = 5.27 Hz, 1H) 8.75 (s, 1H); LCMS m / z = 427 (M + H) ⁺

Example 48
3-((5-Chloro-1- (4-hydroxy-4-methylpentyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4 , 5-c] pyridin-2 (3H) -one (75)
Step 1: 3-((5-Chloro-1- (4-oxypentyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H-imidazo [4 Synthesis of 5-c] pyridin-2 (3H) -one (75-1)

To alcohol 67 (380 mg, 0.89 mmole) dissolved in DCM (30 mL) was added Dess-Martin periodinane (509 mg, 1.35 eq, CAS 87413-09-0). The resulting mixture was stirred at room temperature overnight. Diethyl ether was added (150 mL) and the mixture was stirred for 15 minutes. The mixture was filtered and the filtrate was quickly washed with aqueous Na ₂ S ₂ O ₃ , dried over Na ₂ SO ₄ , filtered and evaporated. The resulting solid was purified by flash chromatography (10% MeOH in DCM) to give aldehyde 75 as a pale yellow solid (218 mg, 58% yield). LCMS m / z = 425 (M + H) ⁺

Step 2: 3-((5-Chloro-1- (4-hydroxy-4-methylpentyl) -1H-imidazo [4,5-b] pyridin-2-yl) methyl) -1-cyclopropyl-1H- Synthesis of imidazo [4,5-c] pyridin-2 (3H) -one (75)

To a solution of ketone 75-1 (210 mg, 0.497 mmole) in THF was added dropwise at 0 ° C. MeLi (0.466 mL, 1.5 eq, 1.6 M in THF). The resulting mixture was stirred at room temperature overnight and then heated at 50 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted with dichloromethane, dried over MgSO4 and concentrated. The residue was prepared by column chromatography using dichloromethane and methanol and then on a RP SunFire Prep C18 OBD-10 μm, 30 × 150 mm with a moving bed (water, 0.25% H ₄ HCO ₃ solution in CH ₃ CN). Purification by HPLC gave 11 mg of the desired compound 75. LCMS m / z = 441 (m + H) ^+
1 H NMR (400 MHz, chloroform-d) δ ppm 0.97-1.05 (m, 2H), 1.11-1.22 (m, 2H), 1.17 (s, 6H), 1.43 -1.53 (m, 2H), 1.74 (br.s., 1H), 1.79-1.91 (m, 2H), 2.82-3.05 (m, 1H), 4. 40 (t, J = 7.5 Hz, 2H), 5.39 (s, 2H), 7.11 (d, J = 5.0 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H) ), 7.64 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 5.0 Hz, 1H), 8.70 (s, 1H).

Example 49
Tests for compound characterization and RSV inhibitory activity are shown in Tables 1-5.

General Experimental Details HPLC-MS analysis was performed using any one of the following:

Method 1:
HPLC measurements were performed using an Agilent 1100 module equipped with a pump, diode-array detector (DAD) (wavelength 220 nm), column heater and column specified below. The stream from the column was split into Agilent MSD series G1946C and G1956A. The MS detector consists of API-ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary pointer voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. The fragmentation voltage was 50V. The drying gas temperature was maintained at 350 ° C. with a flow of 10 L / min. Reverse phase HPLC was performed on a YMC-Pack ODS-AQ, 50 × 2.0 mm 5 mm column with a flow rate of 0.8 mL / min. Two kinds of moving beds (moving bed A: water containing 0.1% TFA, moving bed B: acetonitrile containing 0.05% TFA) were used. Initially 100% A was held for 1 minute. The gradient was then applied to 40% A and 60% B during 4 minutes. A typical infusion dose of 2 mL was used. The oven temperature was 50 ° C. (MS polarity: positive).

Method 2:
HPLC measurements were performed using an Agilent 1100 module equipped with a pump, diode-array detector (DAD) (wavelength 220 nm), column heater and column specified below. The stream from the column was split into Agilent MSD series G1946C and G1956A. The MS detector consists of API-ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary pointer voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. The fragmentation voltage was 50V. The drying gas temperature was maintained at 350 ° C. with a flow of 10 L / min. Reverse phase HPLC was performed on a YMC-Pack ODS-AQ, 50 × 2.0 mm 5 mm column with a flow rate of 0.8 mL / min. Two kinds of moving beds (moving bed A: water containing 0.1% TFA, moving bed B: acetonitrile containing 0.05% TFA) were used. Initially 90% A and 10% B were held for 0.8 minutes. The gradient was then applied to 20% A and 80% B during 3.7 minutes and held for 3 minutes. A typical infusion dose of 2 mL was used. The oven temperature was 50 ° C. (MS polarity: positive).

Method 3:
Column: XTerra MS C18 2.5μ, 4.6 × 50 mm, moving bed A: 0.1% HCOOH in 10 mM NH ₄ OOCH + H ₂ O, moving bed B: operating at column temperature of 50 ° C. using MeOH flow rate 1.5 mL / min. . Gradient conditions: t = 0 min: 65% A, 35% B; t = 3.5 min, 5% A, 95% B; t = 5.5 min: 5% A, 95% B; t = 5. 6 min: 65% A, 35% B; t = 7 min, 65% A, 35% B.

Method 4:
Column: SunFire C18 3.5μ, 4.6 × 100 mm, moving bed A: 0.1% HCOOH in 10 mM NH ₄ OOCH + H ₂ O, moving bed B: operated at a column temperature of 50 ° C. using MeOH flow rate 1.5 mL / min. Gradient conditions: t = 0 min: 65% A, 35% B; t = 7 min, 5% A, 95% B; t = 9.6 min: 5% A, 95% B; t = 9.8 min : 65% A, 35% B; t = 12 minutes, 65% A, 35% B.
NMR spectra are recorded on a Bruker Avance 400 Spectrometer and for ¹ H operating at 400 MHz. Chemical shifts are provided with J values in ppm and Hz. Multiplicity is indicated using abbreviations such as d for doublets, t for triplets, m for multiplets, and the like. Thin layer chromatography (TLC) was performed on 5 × 10 cm aluminum sheets coated with silica gel 60F254 (Merck KGaA).

Antiviral activity Black 96-well clear-bottom microtiter plates (Corning, Amsterdam, the Netherlands) in medium (RPMI medium without phenol red, 10% FBS, 0.04% gentamicin (50 mg / mL) And a series of 4-fold dilutions of the compound in a final volume of 50 μl of 0.5% DMSO] was overfilled using a custom made robotic system. Next, 100 μl of HeLa cell suspension in medium (5 × 10 ⁴ cells / mL) is added to each well, followed by rgRSV224 (50 μl in medium using a multidrop dispenser (Thermo Scientific, Erembodegem, Belgium)). MOI = 0.02) Virus was added. The rgRSV224 virus is a virus that has been engineered to contain an additional GFP gene (Hallak et al, 2000) and is in-licensed from NIH (Bethesda, MD, USA). Media, virus- and mock infection controls were included in each test. Cells were incubated at 37 ° C. in a 5% CO ₂ atmosphere. Viral replication 3 days after virus exposure was quantified by measuring GFP expression in cells by MSM laser microscopy (Tibotec, Beelse, Belgium). EC ₅₀ was defined as the 50% inhibitory concentration for GFP expression. Compounds are incubated for 3 days in a set of parallel white 96-well microtiter plates (Corning) to determine the toxicity of the compounds in HeLa cells using the ATPlite kit (PerkinElmer, Zaventem, Belgium), manufacturer's instructions. According to the measurement of the ATP content of the cells. CC ₅₀ was defined as the 50% concentration for cytotoxicity.

Literature Hallak LK, Spillmann D, Collins PL, Peles ME. Glycosaminoglycan sulfation requirements for respiratory synchronization virus infection. J. Respiratory syncytial virus infection. Virol. 740, 10508-10513 (2000).

Claims (18)

Compounds satisfying Formula I, or prodrugs, N-oxides, addition salts, quaternary amines, metal complexes or stereochemically isomeric forms thereof:

Wherein each X is independently C or N, and at least one X is N;
Each Y is independently C or N;
R ₁ is present when X is C, and R ₁ is H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, N (R ₅ ) ₂ , CO (R ₆ ), CH ₂ NH ₂ , CH ₂ OH, CN, C (= NOH) NH ₂ , C (= NOCH ₃ ) NH ₂ , C (= NH) NH ₂ , CF ₃ , OCF ₃ and B (OH) ₂ ; B (◯ -C ₁ -C ₆ alkyl) selected from ₂ groups;
R ₁ is not present when X is N,
R ₂ is — (CR ₇ R ₈ ) _n —R ₉ ,
R ₃ is selected from the group consisting of H, C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₁₀ alkenyl, SO ₂ -R ₇ , CH ₂ CF ₃ , or contains an oxygen atom A 4-6 membered saturated ring;
R ₄ is present when Y is C and is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, CO (R ₇ ), COO (R ₇ ). Selected from the group consisting of CF ₃ and halogen;
R ₅ is selected from the group consisting of H, C ₁ -C ₆ alkyl, COOCH ₃ and CONHSO ₂ CH ₃ ;
R ₆ is OH, O (C ₁ -C ₆ alkyl), NH ₂ , NHSO ₂ N (C ₁ -C ₆ alkyl) ₂ , NHSO ₂ NHCH ₃ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ Selected from the group consisting of (C ₃ -C ₇ cycloalkyl) and N (C ₁ -C ₆ alkyl);
R ₇ and R ₈ are each independently selected from H, C ₁ -C ₁₀ alkyl and C ₃ -C ₇ cycloalkyl, or R ₇ and R _{8 taken} together are N, S, O Forming a 4- to 6-membered aliphatic ring optionally containing a heteroatom selected from:
R ₉ is H, R ₁₀ , C ₁ -C ₆ alkyl, OH, CN, F, CF ₂ H, CF ₃ , CONR ₇ R ₈ , COOR ₇ , CON (R ₇ ) SO ₂ R ₈ , CON (R _{7) SO 2 N (R 7} R 8), NR 7 R 8, NR 7 COOR 8, OCOR 7, O- _{benzyl, NR 7 SO 2 R 8,} SO 2 NR 7 R 8, SO 2 R 7, OCONR 7 R ₈ , OCONR ₇ R ₁₀ , N (R ₇ ) CON (R ₇ R ₈ ), N (R ₇ ) COOR ₁₀ ; containing phthalimide, 2-methyl-benzothiophene (1,1) dioxide, or oxygen atom Selected from the group consisting of 4-6 membered saturated rings;
n is an integer from 2 to 6;
R ₁₀ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridine or pyrazole, which are optionally selected from CF ₃ , CH ₃ , OCH ₃ , OCF ₃ or halogen. May be substituted with one or more substituents. R ₃ is selected from the group consisting of H, C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₁₀ alkenyl, SO ₂ -R ₇ , or a 4-6 membered saturated ring containing an oxygen atom. And
R ₉ is H, C ₁ -C ₆ alkyl, OH, CN, F, CF ₂ H, CF ₃ , CONR ₇ R ₈ , COOR ₇ , CON (R ₇ ) SO ₂ R ₈ , CON (R ₇ ) SO ₂ Contains N (R ₇ R ₈ ), NR ₇ R ₈ , NR ₇ COOR ₈ , OCOR ₇ , O-benzyl, NR ₇ SO ₂ R ₈ , SO ₂ NR ₇ R ₈ , SO ₂ R ₇ , or oxygen atom 2. A compound according to claim 1 selected from the group consisting of 4 to 6 membered saturated rings.   3. A compound according to claim 1 or 2, wherein one X is N, wherein N is in one of two ortho positions relative to the imidazole ring. The compound according to claim 1, wherein R ₁ is selected from the group consisting of H and halogen. A compound according to any one of the preceding claims, wherein R ₁ in the para position relative to C-N-R ₂ is selected from the group consisting of H, halogen and all other R ₁ are H. R ₇ and R ₈ are H, n is 2-4 The compound according to any one of the preceding claims. R ₉ is selected from the group consisting of OH, F, CF ₂ H, CF ₃ , C ₁ -C ₆ alkyl, SO ₂ R ₇ ,
A compound according to any one of the preceding claims. R ₃ is selected from the group consisting of 4-membered saturated hydrocarbons containing a C ₃ -C ₇ cycloalkyl and oxygen atom A compound according to any one of the preceding claims. A compound according to any one of the preceding claims, wherein R ₃ is cyclopropyl or CH ₂ CF ₃ . One Y is N, the other Y is is C, one Y is N are preferably in the para position relative to the N-R _3, A compound according to any one of the preceding claims . The compound according to any one of the preceding claims, wherein R ₄ on one Y in the para position to N-R ₃ is F. A compound according to any one of the preceding claims, wherein all R ₄ are H.   13. A compound as claimed in any one of claims 1 to 12 for use as a medicament.   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 12 as an active ingredient.   15. A method for the preparation of a pharmaceutical composition as claimed in claim 14, wherein the pharmaceutically acceptable carrier is in a therapeutically effective amount of a compound as claimed in any one of claims 1-12. The method as described above, comprising intimately mixing with.   13. A compound according to any one of claims 1 to 12 for use as a medicament for inhibiting RSV replication. It is a manufacturing method of the compound as described in any one of Claims 1-12, Comprising: According to the following scheme 1, a compound chosen from the group which consists of II-a, II-b, and II-c and compound III are coupled Comprising a step of providing a derivative of formula (I).

All substituents R and X have the meanings given in claim 1 or 2.   Use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for the inhibition of RSV replication.